Pyrazole compound

ABSTRACT

The present invention relates to a novel serotonin reuptake inhibitor which also exhibits 5-HT 2C  antagonistic action (antidepressive and anxiolytic effects), in particular, 5-HT 2C  inverse agonistic action comprising Compound (1): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof
     wherein R 1 , R 2 , R 3  and R 4  are independently hydrogen or C 1-6  alkyl etc.; R 5  is C 4-7  alkyl or —(CR 8 R 9 ) r -E; R 6 , R 7 , R 8  and R 9  are independently hydrogen, fluorine or C 1-6  alkyl; A is C 6-10  aryl or heteroaryl etc.; r is 1, 2, 3 or 4; E is C 3-8  cycloalkyl or C 6-10  aryl etc.; L is oxygen, sulfur or —NR 10 —; n is 1, 2 or 3; R 10  is hydrogen or C 1-6  alkyl etc.; and X is hydrogen or halogen etc.

TECHNICAL FIELD

The present invention relates to a medicament comprising a novelpyrazole derivative or a pharmaceutically acceptable salt thereof as anactive ingredient. In detail, the present invention relates to amedicament for treating depression, anxiety and the like or preventing arelapse thereof, which has 5-HT_(2C) antagonistic action, in particular,5-HT_(2C) inverse agonistic action, and serotonin reuptake inhibitoryaction.

BACKGROUND ART

Depression is a chronic disease which can affect people of all ages.Amongst currently-used various antidepressants, the most successful oneis a selective serotonin reuptake inhibitor (hereinafter, optionallyabbreviated as “SSRI”). SSRIs have a higher serotonin reuptakeinhibitory action than dopamine or noradrenaline reuptake inhibitoryaction. SSRIs include, for example, fluvoxamine, citalopram, sertralineand paroxetine, which play the main role in the drug treatment fordepression.

Such SSRIs have lower side effects, compared with a tricyclicantidepressant (hereinafter, optionally abbreviated as “TCA”) which isknown as a conventional antidepressant, and thus SSRIs are widely usedas a highly safe antidepressant. On the other hand, some problems inSSRIs are also indicated. The problems include, for example, that ittakes a long term of 3 to 8 weeks to exert enough antidepressive action;gastrointestinal symptom such as nausea, vomiting, and diarrhea, andso-called activation syndrome such as initiation or exacerbation inanxiety symptom and restlessness appear as side effects, in particular,early after a SSRI is administered; and the remission rate of thetreatment with a SSRI alone is about 1/3, which is not enough for thetherapeutic effect. Namely, SSRIs show slow and insufficient onset ofthe antidepressive action, but the side effects appear promptly. Hence,the compliance thereof is often adversely affected early after a SSRI isadministered. Furthermore, SSRIs have a problem for increasing a riskfor suicide early after the administration, since the onset of theantidepressive action is slow and then a patient recovers its initiativebefore the patient experiences enough improvement in its depressivesymptom. Accordingly, it has been desired to develop a newantidepressant whose onset of the antidepressive action is prompt andwhose antidepressive action is potent.

It is known that a serotonin 2C (hereinafter, optionally abbreviated as“5-HT_(2C)”) ligand can affect the release of serotonin and dopamine ina rat cerebral cortex (e.g., Neuropsychopharmacology, (2004), 29,1782-1789 (5-HT), Synapse, (2000), 36, 205-221(DA)). The mechanism ofcontrolling the release of a monoamine such as serotonin and dopamine by5-HT_(2C) receptor is thought as mentioned below. Serotonin neuron anddopamine neuron are suppressively controlled by GABA (gamma-aminobutyricacid) neuron in dorsal raphe nucleus and ventral tegmental area whichare each nucleus of origin, respectively. There are 5-HT_(2C) receptorson the GABA neuron. When the receptors are stimulated, the GABA releaseis promoted to inhibit serotonin neuron and dopamine neuron. Namely,when 5-HT_(2C) receptors are inhibited, it is thought that the GABArelease is suppressed in nucleus of origin to promote the release of amonoamine such as serotonin and dopamine in prefrontal cortexes orhippocampi which are projection targets of each neuron. In addition, ithas been reported that compounds having the inverse agonistic action for5-HT_(2C) receptor exhibit more potent promoting action of the monoaminerelease than compounds having only the inhibitory action thereof (e.g.,The Journal of Neuroscience, (2004), 24, 3235-3241).

It has been reported that a combination of a SSRI and a 5-HT_(2C)antagonist/inverse agonist can early increase the serotonin level in ratprefrontal cortexes compared with the case of a SSRI alone (e.g.,Neuropsychopharmacology, (2004), 29, 1782-1789). Accordingly, a compoundhaving both the serotonin reuptake inhibitory action and the 5-HT_(2C)antagonistic/inverse agonistic action is expected to exhibit theantidepressive action for a patient suffering from depression at anearly stage.

On the other hand, as a trial to increase the antidepressive action, ithas been reported that a combination therapy of a SSRI and amood-stabilizing drug such as lithium carbonate and tri-iodotyrosine, aswell as a combination therapy of a conventional antidepressant havingthe serotonin reuptake inhibitory action such as a TCA and a SSRI, and adopamine agonist such as bromocriptine are effective for a patientsuffering from depression who is resistant to the monotherapy of a SSRI(e.g., Biol psychiatry (1996), 40, 152). Accordingly, the activation ofboth serotonin neuron and dopamine neuron is expected to exhibit apotent antidepressive action for a patient suffering from wide rangedepression.

A SSRI in clinical practice is useful as an anxiolytic drug, but ittakes several weeks for the onset of its therapeutic effect as is thecase in the therapy of depression, which is a problem. In addition, ithas been reported that a 5-HT_(2C) antagonist or inverse agonist alsoexhibits the anxiolytic action in a variety of anxious animal models(e.g., British Journal of Pharmacology, (1996), 117, 427-434, EuropeanJournal of Pharmacology, (2006) 553, 171-184). Accordingly, a compoundhaving both serotonin reuptake inhibitory action and 5-HT_(2C)antagonistic/inverse agonistic action is expected to exhibit a potentanxiolytic action.

Amongst patients suffering from depression, it is known that the rate ofpatients suffering from depression who are accompanied with anxietysymptom is high, and additionally the depression symptom accompaniedwith anxiety symptom is apt to be protracted, thus patients sufferingfrom depression who are accompanied with anxiety symptom are apt to beresistant to the therapy with a SSRI (e.g., Psychological Medicine,(2004), 34, 1299-1308). Accordingly, an antidepressant having a potentanxiolytic action is thought to be very useful in the depressiontherapy.

From the above-mentioned viewpoint, a compound having both the serotoninreuptake inhibitory action and the 5-HT_(2C) antagonistic action, inparticular, the 5-HT_(2C) inverse agonistic action can activate bothserotonin neuron and dopamine neuron by increasing the amount ofserotonin released by the serotonin reuptake inhibitory action andindirectly increasing the amount of dopamine released by the 5-HT_(2C)antagonistic action. Accordingly, such compound is expected to be a newantidepressant useful for a patient suffering from wide rangedepression, which exhibits prompt onset of its action and has a potentantidepressive action and anxiolytic action. It has been desired todevelop a new medicament comprising such a new compound. For example, US2007/0105843 A discloses a combination of a medicament having theserotonin reuptake inhibitory action and a medicament having the5-HT_(2C) antagonistic action and use of a compound having both theserotonin reuptake inhibitory action and the 5-HT_(2C) antagonisticaction as an antidepressant or an anxiolytic drug, but does notspecifically disclose any compounds having both the serotonin reuptakeinhibitory action and the 5-HT_(2C) antagonistic action, in particular,5-HT_(2C) inverse agonistic action.

For example, Patent References 1 to 5 as mentioned below report acompound wherein an aminomethyl group is attached at the 3-position ofthe pyrazole ring.

Patent Reference 1 discloses, for example, a 3-aminomethylpyrazolederivative of the following formula P-1. However, the structure thereofdiffer from that of the present compound in that the compound of PatentReference 1 has an isopropyl group and a substituted phenoxy group as asubstituent at 1- and 5-position of the pyrazole ring, respectively. Inaddition, Patent Reference 1 is directed to a HIV reverse transcriptaseinhibitor, but neither discloses nor suggests serotonin reuptake action,5-HT_(2C) antagonistic action or 5-HT_(2C) inverse agonistic action.

Patent Reference 2 discloses, for example, a 3-aminomethylpyrazolederivative of the following formula P-2. However, the structure thereofdiffer from that of the present compound in that the compound of PatentReference 2 has a isopropyl group, a pyridylmethyl group, and asubstituted phenylthio group as a substituent at 1-, 4- and 5-positionof the pyrazole ring, respectively. In addition, Patent Reference 2 isdirected to a HIV reverse transcriptase inhibitor, but neither disclosesnor suggests serotonin reuptake action, 5-HT_(2C) antagonistic action or5-HT_(2C) inverse agonistic action.

Patent Reference 3 discloses, for example, a 3-aminomethylpyrazolederivative of the following formula P-3. However, the structure thereofdiffer from that of the present compound in that the compound of PatentReference 3 has a cyclopropyl group and a substituted phenyl group as asubstituent at 1- and 5-position of the pyrazole ring, respectively. Inaddition, Patent Reference 3 is directed to a nociceptin inhibitor, butneither discloses nor suggests serotonin reuptake action, 5-HT_(2C)antagonistic action or 5-HT_(2C) inverse agonistic action.

Patent Reference 4 discloses, for example, a 3-aminomethylpyrazolederivative of the following formula P-4. However, the structure thereofdiffer from that of the present compound in that the compound of PatentReference 4 has a substituted phenyl group as a substituent at5-position of the pyrazole ring. In addition, Patent Reference 4discloses the pyrazole derivative as a synthetic intermediate, butneither discloses nor suggests serotonin reuptake action, 5-HT_(2C)antagonistic action or 5-HT_(2C) inverse agonistic action.

Patent Reference 5 and Patent Reference 6 disclose, for example, a3-piperazinylmethylpyrazole derivative of the following formula P-5.However, the structure thereof differ from that of the present compoundin that the compound of Patent References 5 and 6 have a biphenyl groupand a substituted phenyl group as a substituent at 1- and 5-position ofthe pyrazole ring, respectively. In addition, Patent Reference 6discloses that the pyrazole derivative has both 5-HT_(2C) antagonisticaction and 5-HT_(2A) antagonistic action, but neither discloses norsuggests serotonin reuptake action.

PRIOR ART DOCUMENTS Patent Reference

[Patent Reference 1] WO 2004/074257

[Patent Reference 2] WO 2002/100853

[Patent Reference 3] WO 2007/037513

[Patent Reference 4] WO 2009/004171

[Patent Reference 5] WO 2003/031435

[Patent Reference 6] WO 2004/089931

SUMMARY OF INVENTION Technical Problem

The purpose of the present invention is to provide a new serotoninreuptake inhibitor having 5-HT_(2C) antagonistic action, in particular,5-HT_(2C) inverse agonistic action, which is useful as a medicament fortreating depression or anxiety (anxiety disorder), or preventing arelapse thereof.

Solution to Problem

The present inventors have extensively studied to solve the aboveproblem and then have found that a compound having a pyrazole structureor a pharmaceutically acceptable salt thereof has both 5-HT_(2C)antagonistic action (in particular, 5-HT_(2C) inverse agonistic action)and serotonin reuptake inhibitory action, which is useful as amedicament for treating depression or anxiety, or preventing a relapsethereof. Based upon the new findings, the present invention has beencompleted. The present invention relates to the following inventions.

[1] A compound of Formula (1):

[hereinafter, optionally referred to as “the compound of Formula (1)” or“Compound (1)” ]or a pharmaceutically acceptable salt thereof wherein

R¹ and R² are independently selected from the group consisting ofhydrogen atom, a C₁₋₆ alkyl group and a C₃₋₈ cycloalkyl group,

R³ and R⁴ are independently selected from the group consisting ofhydrogen atom and a C₁₋₆ alkyl group,

R⁵ is an optionally-substituted C₄₋₇ alkyl group or —(C⁸R⁹)_(r)-E,

R⁶, R⁷, R⁸ and R⁹ are independently selected from the group consistingof hydrogen atom, fluorine atom and an optionally-substituted C₁₋₆ alkylgroup,

A is an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group,

r is 1, 2, 3 or 4,

E is an optionally-substituted C₃₋₈ cycloalkyl group, anoptionally-substituted C₄₋₈ cycloalkenyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 heteroatoms independently selected from the groupconsisting of oxygen atom and sulfur atom as a constituent atom of thering, an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group,

L is oxygen atom, sulfur atom or —NR¹⁰—,

n is 1, 2 or 3,

R¹⁰ is hydrogen atom, a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group, and

X is hydrogen atom, a C₁₋₆ alkyl group optionally-substituted withfluorine atom or a halogen atom.

[2] The compound of [1] or a pharmaceutically acceptable salt thereofwherein

R¹, R² and R³ are independently selected from the group consisting ofhydrogen atom and methyl group, and

R⁴ is hydrogen atom.

[3] The compound of [1] or [2] or a pharmaceutically acceptable saltthereof wherein A is an optionally-substituted C₆₋₁₀ aryl group.

[4] The compound of any one of [1] to [3] or a pharmaceuticallyacceptable salt thereof wherein X is hydrogen atom.

[5] The compound of any one of [1] to [4] or a pharmaceuticallyacceptable salt thereof wherein L is oxygen atom.

[6] The compound of any one of [1] to [5] or a pharmaceuticallyacceptable salt thereof wherein n is 1.

[7] The compound of any one of [1] to [6] or a pharmaceuticallyacceptable salt thereof wherein

R¹, R³ and R⁴ are hydrogen atom, and

R² is methyl group.

[8] The compound of any one of [1] to [7] or a pharmaceuticallyacceptable salt thereof wherein R⁶, R⁷, R⁸ and R⁹ are hydrogen atom.

[9] The compound of any one of [1] to [8] or a pharmaceuticallyacceptable salt thereof wherein E is an optionally-substituted C₃₋₈cycloalkyl group, an optionally-substituted 5- to 10-membered saturatedheterocyclic group which comprises 1 to 3 oxygen atoms as a constituentatom of the ring, or an optionally-substituted phenyl group.

[10] The compound of any one of [1] to [9] or a pharmaceuticallyacceptable salt thereof wherein E is an optionally-substituted C₃₋₈cycloalkyl group.

[11] The compound of any one of [1] to [10] or a pharmaceuticallyacceptable salt thereof wherein r is 1 or 2.

[12] The compound of any one of [1] to [8] or a pharmaceuticallyacceptable salt thereof wherein R⁵ is an optionally-substituted C₄₋₇alkyl group.

[13] The compound of [1] wherein the compound of Formula (1) is any oneof the following compounds, or a pharmaceutically acceptable saltthereof:

-   1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 5-   1-{1-(cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 20-   1-{1-(cyclohexylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 21-   1-{1-(cyclohexylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 22-   1-{5-[(2-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 23-   1-{5-[(3-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 24-   1-{1-(cyclohexylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 26-   1-{1-(cyclohexylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 27-   1-{1-(cyclohexylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 29-   1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 30-   1-{1-(cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 31-   1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 33-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 34-   1-{1-(cyclohexylmethyl)-5-[(2-fluoro-5-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 35-   1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 37-   1-{1-(cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 38-   1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 39-   1-[5-(benzyloxy)-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 4-   1-{1-(cyclopentylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 135-   1-{1-(cyclopentylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 136-   1-{1-(cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 137-   1-{5-[(2-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 138-   1-{5-[(3-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 139-   1-{1-(cyclopentylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 141-   1-{1-(cyclopentylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 142-   1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 144-   1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 145-   1-{1-(cyclopentylmethyl)-5-[(4-fluoro-2-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 146-   1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 147-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 148-   1-{1-(cyclopentylmethyl)-5-[(2-fluoro-5-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 149-   1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 150-   1-{1-(cyclopentylmethyl)-5-[(2,5-dichloro    benzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine; Example 151-   1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 152-   1-[5-(benzyloxy)-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 264-   1-{5-[(3-chlorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 265-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 266-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3,3-dimethyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 267-   1-[5-(benzyloxy)-1-(3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 268-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 269-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 270-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methoxy-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 274-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 275-   1-{1-(cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 280-   1-{1-(cyclohexylmethyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;-   1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 315-   N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluoro-benzyl)oxy]-1H-pyrazol-3-yl}methanamine;    Example 283-   1-{1-(3,3-dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 284-   1-{1-(4-fluorobenzyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 218-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-fluorobenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 219-   1-{1-(4-fluorobenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;-   1-{5-[(2-fluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 228-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 230-   N-methyl-1-{1-(4-methylbenzyl)-5-[(2,4,5-trifluoro-benzyl)oxy]-1H-pyrazol-3-yl}methanamine;    Example 286-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    no Examples-   1-{1-(4-methoxybenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 285-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 131-   1-{5-[(4-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 369-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methyl-propyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 256-   1-{1-(2,2-dimethylpropyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 375-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 258-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2,2-dimethyl-propyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 259-   1-{5-[(2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 381-   1-{5-[(4-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 383-   1-(5-[(4-fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)-cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanamine;    Example 446-   1-(5-[(2,5-difluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methyl-methanamine;    Example 447-   1-(5-[(5-chloro-2-fluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethan-amine;    Example 448-   (−)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 474-   (+)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 475-   (−)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 476-   (+)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 477-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-fluoro-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 481 or,-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 482.

[14] A medicament comprising the compound of any one of [1] to [13] or apharmaceutically acceptable salt thereof as an active ingredient.

[15] The medicament of [14] which is used for treating depression oranxiety, or preventing a relapse thereof.

[16] A serotonin reuptake inhibitor comprising the compound of any oneof [1] to [13] or a pharmaceutically acceptable salt thereof as anactive ingredient.

[17] A pharmaceutical composition comprising the compound of any one of[1] to [13] or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Effect of Invention

The present invention can provide a serotonin reuptake inhibitor having5-HT_(2C) antagonistic action, in particular 5-HT_(2C) inverse agonisticaction, which comprises a pyrazole derivative or a pharmaceuticallyacceptable salt thereof as an active ingredient. The serotonin reuptakeinhibitor of the present invention exhibits antidepressive andanxiolytic effects, and is thus useful as a medicament for treatingdepression and anxiety or preventing a relapse thereof.

DESCRIPTION OF EMBODIMENTS

Throughout the description, for example, C₁₋₆, C₁₋₄, and C₆ indicatethat the number of carbon atom is 1 to 6, 1 to 4, and 6, respectively.As used herein, a similar definition of carbon having a differentsubscript number is also meant in the same manner.

The “halogen atom” used herein includes fluorine atom, chlorine atom,bromine atom and iodine atom.

The “C₁₋₆ alkyl group” used herein means a straight- or branched-chainsaturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, andspecifically includes methyl group, ethyl group, propyl group, n-butylgroup, n-pentyl group, n-hexyl group, isopropyl group, sec-butyl group,isobutyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutylgroup, 3-methylbutyl group, 1-ethylpropyl group and the like. The C₁₋₆alkyl group includes preferably a C₁₋₄ alkyl group, more preferably aC₁₋₃ alkyl group.

The “C₄₋₇ alkyl group” used herein means a straight- or branched-chainsaturated aliphatic hydrocarbon group having 4 to 7 carbon atoms, andspecifically includes n-butyl group, n-pentyl group, n-hexyl group,n-heptyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group,1-methyl-1-ethylpropyl group, 1,1-diethylpropyl group,2,2-dimethylpropyl group, sec-butyl group, isobutyl group, tert-butylgroup, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group,2-ethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group,2-methyl-2-ethylbutyl group and the like. The C₄₋₇ alkyl group includespreferably a C₄₋₆ alkyl group, and specifically includes isobutyl group,2,2-dimethylpropyl group, 3-methylbutyl group, 3,3-dimethylbutyl groupand 2-ethylbutyl group.

The “C₆₋₁₀ aryl group” used herein means a monocyclic or bicyclicaromatic hydrocarbon ring group having 6 to 10 carbon atoms, andincludes preferably a C₆ or C₁₀ aryl group. The C₆₋₁₀ aryl groupspecifically includes phenyl group, 1- and 2-naphthyl group, and thelike.

The “5- to 10-membered heteroaryl group” means a 5- to 10-memberedmonocyclic or bicyclic aromatic heterocyclic group comprising 1 to 3heteroatoms independently selected from the group consisting of nitrogenatom, oxygen atom and sulfur atom, wherein the position of theheteroatom in the heteroaryl group and the bonding position of theheteroaryl group are not limited as long as they are chemically stable.The 5- to 10-membered heteroaryl group specifically includes furylgroup, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group,thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group,furazanyl group, oxadiazolyl group, triazolyl group, tetrazolyl group,pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group,indolyl group, quinolyl group, isoquinolyl group, quinazolinyl group,imidazo[2,1-b] [1,3]thiazolyl group, benzofuryl group, indolizinylgroup, indazolyl group and the like; preferably 5- and 6-memberedmonocyclic heteroaryl group and 9- and 10-membered bicyclic heteroarylgroup. The 5- to 10-membered heteroaryl group also includes an N-oxideform thereof wherein the nitrogen atom of the heteroaryl group isoxidized.

Furthermore, the C₆₋₁₀ aryl group and the 5- to 10-membered heteroarylgroup may each form a condensed ring with a C₃₋₈ cycloalkyl, C₄₋₈cycloalkenyl or 5- to 10-membered saturated heterocyclic group. In thiscase, the C₆₋₁₀ aryl group forming a condensed ring specificallyincludes the following formulae:

wherein the bonding position of the benzene ring is not limited as longas it is chemically stable.

Furthermore, the 5- to 10-membered heteroaryl group forming a condensedring specifically includes the following formulae:

wherein the bonding position of the pyridine ring is not limited as longas it is chemically stable.

The condensed ring may have the below-mentioned substituent which isshown as a substituent for each of the rings forming the condensed ring.

The “C₃₋₈ cycloalkyl group” used herein means a monocyclic or bicyclicsaturated aliphatic hydrocarbon ring group having 3 to 8 carbon atoms;and specifically includes cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctylgroup, bicyclo[2,2,1]heptyl group, bicyclo[3,2,0]heptyl group, and thelike. The C₃₋₈ cycloalkyl group includes preferably a monocyclic C₃₋₆cycloalkyl group.

The “C₄₋₈ cycloalkenyl group” used herein means a monocyclic or bicyclicunsaturated aliphatic hydrocarbon ring group having 4 to 8 carbon atomswith 1 or 2 double bonds, and specifically includes cyclobutenyl group,cyclopentenyl group, cyclohexenyl group, and cycloheptenyl group. Theposition of the double bond in the ring is not limited. The cycloalkenylgroup includes preferably C₅ and C₆ cycloalkenyl groups.

The “5- to 10-membered saturated heterocyclic group which comprises 1 to3 heteroatoms independently selected from the group consisting of oxygenatom and sulfur atom as a constituent atom of the ring” used hereinmeans a 5- to 10-membered monocyclic or bicyclic saturated aliphaticheterocyclic group comprising 1 to 3 heteroatoms independently selectedfrom the group consisting of oxygen atom and sulfur atom, wherein theposition of the heteroatom in the heteroaryl group and the bondingposition of the heteroaryl group are not limited as long as they arechemically stable. The saturated heterocyclic group includes preferably5- to 8-membered saturated heterocyclic groups, more preferably 5- and6-membered saturated heterocyclic groups. The 5- to 10-memberedsaturated heterocyclic group specifically includes tetrahydrofurylgroup, tetrahydro-2H-pyranyl group, 1,4-dioxanyl group,tetrahydrothienyl group, tetrahydro-2H-thiopyranyl group, and bicyclicgroups of the following formulae:

wherein the bonding position of the ring is not limited as long as it ischemically stable. The 5- to 10-membered saturated heterocyclic group ispreferably a saturated heterocyclic group comprising 1 or 2 oxygen atomsin the ring, and includes, for example, tetrahydrofuryl group,tetrahydro-2H-pyranyl group, 1,4-dioxanyl group,7-oxabicyclo[2,2,1]heptyl group, and 2-oxabicyclo[2,2,2]octyl group.

The C₃₋₈ cycloalkyl group, C₄₋₈ cycloalkenyl group and 5- to 10-memberedsaturated heterocyclic group may each form a condensed ring with a C₆₋₁₀aryl or 5- to 10-membered heteroaryl. The condensed ring specificallyincludes the following formulae:

wherein the bonding position of the C₃₋₈ cycloalkyl group, C₄₋₈cycloalkenyl group and 5- to 10-membered saturated heterocyclic group isnot limited as long as it is chemically stable. The condensed ring mayhave the below-mentioned substituent which is shown as a substituent foreach of the rings forming the condensed ring.

The substituents of the “optionally-substituted C₆₋₁₀ aryl group” and“optionally-substituted 5- to 10-membered heteroaryl group” includes,for example, a halogen atom, a C₁₋₆ alkyl group optionally substitutedwith fluorine atom, a C₁₋₆ alkyloxy group optionally substituted withfluorine atom, hydroxy group, a C₁₋₆ alkylthio group, a C₆₋₁₀ aryloxygroup, a C₆₋₁₀ arylthio group, cyano group, —CO₂R¹¹, —SO₂R¹¹,—NR¹⁰SO₂R¹¹, —OSO₂R¹¹, —COR¹², —SO₂NR¹²R¹³, —CONR¹²R¹³, —NR¹²R¹³,—NR¹⁰CONR¹²R¹³, —NR¹⁰COR¹², —CR¹²═N(OR¹¹)—, oxime group, a C₃₋₈cycloalkyl group, a C₆₋₁₀ aryl group, and a 5- to 10-membered heteroarylgroup (wherein R¹⁰ is the same as defined in the above [1], R¹¹ is aC₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group, an aryl group or a heteroarylgroup, and R¹² and R¹³ are independently selected from the groupconsisting of hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkylgroup, an aryl group and a heteroaryl group; and the aryl, heteroaryl,aryloxy and arylthio groups in R¹¹, R¹² and R¹³ may be each furthersubstituted with halogen atom, a C₁₋₆ alkyl group, hydroxy group or aC₁₋₆ alkyloxy group). The substituents include preferably a halogenatom, a C₁₋₆ alkyl group optionally substituted with fluorine atom, aC₁₋₆ alkyloxy group optionally substituted with fluorine atom, hydroxygroup, a C₁₋₆ alkylthio group and cyano group; and more preferablyfluorine atom, chlorine atom, bromine atom, methyl group, ethyl group,isopropyl group, trifluoromethyl group, methoxy group, ethoxy group,isopropoxy group, trifluoromethoxy group, difluoromethoxy group, andcyano group. As used herein, one or more of the same or differentsubstituents may exist at any position as long as the substitution ispossible.

The substituents of the “optionally-substituted C₁₋₆ alkyl group” and“optionally-substituted C₄₋₇ alkyl group” include, for example, fluorineatom, hydroxy group, and a C₁₋₆ alkyloxy group optionally substitutedwith fluorine atom. As used herein, one or more of the same or differentsubstituents may exist at any position as long as the substitution ispossible.

The substituents of the “optionally-substituted C₃₋₈ cycloalkyl group”,“optionally-substituted. C₄₋₈ cyclo-alkenyl group” and“optionally-substituted 5- to 10-membered saturated heterocyclic group”include, for example, fluorine atom, a C₁₋₆ alkyl group optionallysubstituted with fluorine atom, hydroxy group, and a C₁₋₆ alkyloxy groupoptionally substituted with fluorine atom. As used herein, one or moreof the same or different substituents may exist at any position as longas the substitution is possible.

The “C₁₋₆ alkyloxy group” used herein means an oxy group substitutedwith the above-defined “C₁₋₆ alkyl group”, and specifically includesmethoxy group, ethoxy group, propoxy group, isopropoxy group,1-methylethoxy group, n-butoxy group, sec-butoxy group, tert-butoxygroup, 1-methylpropoxy group, 2-methylpropoxy group, 1,1-dimethylethoxygroup, pentyloxy group, and hexyloxy group. The C₁₋₆ alkyloxy groupincludes preferably a C₁₋₄ alkyloxy group, and includes, for example,methoxy group, ethoxy group and isopropoxy group.

The “C₁₋₆ alkylthio group” used herein means a thio group substitutedwith the above-defined “C₁₋₆ alkyl group” and includes, for example,methylthio group, ethylthio group, propylthio group, 1-methylethylthiogroup, butylthio group, 1-methylpropylthio group, 2-methylpropylthiogroup, 1,1-dimethylethylthio group, pentylthio group, and hexylthiogroup. The C₁₋₆ alkylthio group includes preferably a C₁₋₄ alkylthiogroup.

The “—CONR¹²R¹³” used herein includes, for example, carbamoyl group,methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group,isopropylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoylgroup, and methylethylcarbamoyl group.

The “—CO₂R¹¹” used herein includes, for example, methoxycarbonyl group,ethoxycarbonyl group, propoxy-carbonyl group, butoxycarbonyl group, andtert-butoxy-carbonyl group.

The “—COR¹²” used herein includes, for example, acetyl group, propionylgroup, butyryl group, isobutyryl group, valeryl group, isovaleryl group,pivaloyl group, pentanoyl group, isopentanoyl group, neopentanoyl group,and hexanoyl group.

The “—SO₂R¹¹” used herein includes, for example, methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, andtert-butylsulfonyl group.

The “—NR¹⁰SO₂R¹¹” used herein includes, for example, methylsulfonylamidegroup, ethylsulfonylamide group, propylsulfonylamide group,butylsulfonylamide group, and tert-butylsulfonylamide group.

The “—NR¹⁰CONR¹²R¹³” used herein includes, for example, methylureidogroup, ethylureido group, and propylureido group.

The “—NR¹²R¹³” used herein includes, for example, amino group,methylamino group, ethylamino group, propylamino group, dimethylaminogroup, diethylamino group, and methylethylamino group.

The “—NR¹⁰COR¹²” used herein includes, for example, acetylamino group,ethylcarbonylamino group, propyl-carbonylamino group,isopropylcarbonylamino group, butylcarbonylamino group,isobutylcarbonylamino group, benzoylamino group, and 1- and2-naphthoylamino group.

The “—OSO₂R¹¹” used herein includes, for example, methylsulfonyloxygroup, ethylsulfonyloxy group, propyl-sulfonyloxy group,butylsulfonyloxy group, and tert-butyl-sulfonyloxy group.

The “—SO₂NR¹²R¹³” used herein includes, for example, methylaminosulfonylgroup, ethylaminosulfonyl group, propylaminosulfonyl group,butylaminosulfonyl group, and tert-butylaminosulfonyl group.

The “—CR¹²═N(OR¹¹)—” used herein includes, for example,N-hydroxyiminoethyl group, N-hydroxy-1-iminopropyl group,N-methoxyiminoethyl group, N-methoxy-1-iminopropyl group,N-ethoxyiminoethyl group, and N-ethoxy-1-iminopropyl group.

Among the present compound represented as Formula (1), the substituentsthereof are preferably as follows.

R¹ and R² are independently selected from the group consisting ofhydrogen atom, a C₁₋₆ alkyl group and a C₃₋₈ cycloalkyl group;preferably hydrogen atom and a C₁₋₃ alkyl group; more preferably eitherof R¹ and R² is hydrogen atom, and the other is a C₁₋₃ alkyl group.

R¹ and R² specifically include hydrogen atom, methyl group, ethyl group,propyl group, isopropyl group and cyclopropyl group; preferably eitherof R¹ and R² is hydrogen atom, and the other is methyl group.

R³ and R⁴ are independently selected from the group consisting ofhydrogen atom and a C₁₋₆ alkyl group, preferably hydrogen atom and aC₁₋₃ alkyl group.

R³ and R⁴ specifically include hydrogen atom, methyl group and ethylgroup; preferably both of R³ and R⁴ are hydrogen atom.

R⁵ is an optionally-substituted C₄₋₇ alkyl group or —(CR⁸R⁹)_(r)-E.

The C₄₋₇ alkyl group of R⁵ specifically includes n-butyl group, n-pentylgroup, n-hexyl group, n-heptyl group, 1-ethylpropyl group,1,1-dimethylpropyl group, 1-methyl-1-ethylpropyl group,1,1-diethylpropyl group, 2,2-dimethylpropyl group, sec-butyl group,isobutyl group, tert-butyl group, 1-methylbutyl group, 2-methylbutylgroup, 3-methylbutyl group, 2-ethylbutyl group, 2,2-dimethylbutyl group,3,3-dimethylbutyl group, 2-methyl-2-ethylbutyl group and the like;preferably isobutyl group, 2,2-dimethylpropyl group, 3-methylbutylgroup, 3,3-dimethylbutyl group and 2-ethylbutyl group.

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen atom, fluorine atom and an optionally-substituted C₁₋₆ alkylgroup; preferably hydrogen atom and a C₁₋₃ alkyl group; more preferablyboth of R⁸ and R⁹ are hydrogen atom. R⁸ and R⁹ specifically includehydrogen atom, methyl group, ethyl group, and hydroxymethyl group.

r is 1, 2, 3 or 4; preferably 1, 2 or 3; more preferably 1l or 2; evenmore preferably 1.

E is an optionally-substituted C₃₋₈ cycloalkyl group, anoptionally-substituted C₄₋₈ cycloalkenyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 heteroatoms independently selected from the groupconsisting of oxygen atom and sulfur atom as a constituent atom of thering, an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group; preferably anoptionally-substituted C₃₋₈ cycloalkyl group, an optionally-substituted5- to 10-membered saturated heterocyclic group which comprises 1 to 3heteroatoms independently selected from the group consisting of oxygenatom and sulfur atom as a constituent atom of the ring, anoptionally-substituted C₆₋₁₀ aryl group or an optionally-substituted 5-to 10-membered heteroaryl group; more preferably anoptionally-substituted C₃₋₈ cycloalkyl group, an optionally-substituted5- to 10-membered saturated heterocyclic group which comprises 1 to 3heteroatoms independently selected from the group consisting of oxygenatom and sulfur atom as a constituent atom of the ring, or anoptionally-substituted C₆₋₁₀ aryl group; even more preferably anoptionally-substituted C₃₋₈ cycloalkyl group or anoptionally-substituted C₆₋₁₀ aryl group.

The substituents of the C₆₋₁₀ aryl group and 5- to 10-memberedheteroaryl group in E include, for example, (i) halogen atoms such asfluorine atom and chlorine atom, (ii) C₁₋₆ alkyl groups such as methylgroup, ethyl group, and propyl group, (iii) C₁₋₆ alkyloxy groups such asmethoxy group, ethoxy group, and isopropoxy group, (iv) C₁₋₆ alkylthiogroups such as methylthio group and ethylthio group, (v) cyano group,(vi) trifluoromethyl group, (vii) trifluoromethoxy group, (viii) hydroxygroup, and (ix) difluoromethoxy group; preferably fluorine atom,chlorine atom, methyl group, and methoxy group. As used herein, one ormore of the same or different substituents may exist at any position aslong as the substitution is possible.

E specifically includes phenyl group (preferably substituted at the4-position), cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group, tetrahydrofuryl group,tetrahydro-2H-pyranyl group, 1,4-dioxanyl group, tetrahydrothienylgroup, tetrahydro-2H-thiopyranyl group, and bicyclic groups of thefollowing formulae:

wherein the bonding position of the bicyclic ring is not limited as longas it is chemically stable, in which the above-listed groups may beoptionally substituted with a substituent selected from the groupconsisting of halogen atom, cyano group, an optionally-substituted C₁₋₆alkyl group and an optionally-substituted C₁₋₆ alkyloxy group. Eincludes preferably phenyl group, 4-fluorophenyl group, 4-chlorophenylgroup, 4-methylphenyl group, 4-ethylphenyl group, 4-methoxyphenyl group,4-ethoxyphenyl group, 4-isopropoxyphenyl group, 4-trifluoromethylphenylgroup, cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, and groups of the following formulae:

wherein * is a bonding position.

R⁶ and R⁷ are independently selected from the group consisting ofhydrogen atom, fluorine atom and an optionally-substituted C₁₋₆ alkylgroup; preferably hydrogen atom and fluorine atom; more preferably bothof R⁶ and R⁷ are hydrogen atom. R⁶ and R⁷ specifically include hydrogenatom, fluorine atom, and methyl group.

A is an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group; preferably anoptionally-substituted C₆₋₁₀ aryl group. The optionally-substitutedC₆₋₁₀ aryl group is preferably an optionally-substituted C₆ or C₁₀ arylgroup, more preferably an optionally-substituted C₆ aryl group. Theoptionally-substituted 5- to 10-membered heteroaryl group is preferablyan optionally-substituted 5- or 6-, or 9- or 10-membered heteroarylgroup; more preferably an optionally-substituted 5- or 6-memberedheteroaryl group.

Specific examples of A include preferably an optionally-substitutedphenyl group and an optionally-substituted 1- and 2-naphthyl group; morepreferably an optionally-substituted phenyl group.

The substituents of the optionally-substituted C₆₋₁₀ aryl group,optionally-substituted 5- to 10-membered heteroaryl group,optionally-substituted phenyl group and optionally-substituted 1- or2-naphthyl group in A include, for example, (i) a halogen atom such asfluorine atom and chlorine atom, (ii) a C₁₋₆ alkyl group optionallysubstituted with fluorine atom such as methyl group, ethyl group, propylgroup, and trifluoromethyl group, (iii) a C₁₋₆ alkyloxy group optionallysubstituted with fluorine atom such as methoxy group, ethoxy group,isopropoxy group, and trifluoromethoxy group, (iv) a C₁₋₆ alkylthiogroup such as methylthio group and ethylthio group, (v) cyano group, and(vi) hydroxy group; preferably fluorine atom, chlorine atom, methylgroup and methoxy group; more preferably fluorine atom and chlorineatom. As used herein, one or more of the same or different substituentsmay exist at any position as long as the substitution is possible. Inaddition, the C₆-10 aryl group and the 5- to 10-membered heteroarylgroup may form a fused ring with a C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl or5- to 10-membered saturated heterocyclic group.

The optionally-substituted phenyl group includes, for example, thefollowing formulae:

wherein

R¹⁴, R¹⁵ and R¹⁶ are independently selected from the group consisting ofa halogen atom, a C₁₋₆ alkyl group optionally substituted with fluorineatom, a C₁₋₆ alkyloxy group optionally substituted with fluorine atom,and cyano group, and

* is a bonding position.

L is oxygen atom, sulfur atom or —NR¹⁰—; preferably oxygen atom orsulfur atom; more preferably oxygen atom.

R¹⁰ is hydrogen atom, a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group;preferably hydrogen atom or a C₁₋₆ alkyl group; more preferably hydrogenatom or a C₁₋₃ alkyl group.

R¹⁰ specifically includes hydrogen atom, methyl group, ethyl group,n-propyl group, butyl group, pentyl group, hexyl group, cyclopropylgroup, cyclobutyl group, cyclo-pentyl group and cyclohexyl group;preferably hydrogen atom and methyl group.

X is hydrogen atom, a C₁₋₆ alkyl group optionally substituted withfluorine atom or a halogen atom, and includes, for example, hydrogenatom, fluorine atom, chlorine atom and methyl group. X is preferablyhydrogen atom or a halogen atom, more preferably hydrogen atom.

n is 1, 2 or 3; preferably 1 or 2; more preferably 1.

The present compounds include preferably the following compounds orpharmaceutically acceptable salts thereof.

In one preferred embodiment, the present compound includes a compoundwherein

R¹ and R² are independently selected from the group consisting ofhydrogen atom and a C₁₋₆ alkyl group,

R³ and R⁴ are independently selected from the group consisting ofhydrogen atom and methyl group,

R⁵ is an optionally-substituted C₄₋₇ alkyl group or —(CR⁸R⁹)_(r)-E,

R⁶ and R⁷ are hydrogen atom,

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen atom, fluorine atom and an optionally-substituted C₁₋₆ alkylgroup,

A is an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group,

r is 1 or 2,

E is an optionally-substituted C₃₋₈ cycloalkyl group, anoptionally-substituted C₄₋₈ cycloalkenyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 heteroatoms independently selected from the groupconsisting of oxygen atom and sulfur atom as a constituent atom of thering, an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group,

L is oxygen atom or sulfur atom,

n is 1, and

X is hydrogen atom, a C₁₋₆ alkyl group optionally substituted withfluorine atom or a halogen atom.

Preferably, the present compound includes a compound wherein

R¹ and R² are independently selected from the group consisting ofhydrogen atom and a C₁₋₆ alkyl group,

R³ and R⁴ are hydrogen atom,

R⁵ is an optionally-substituted C₄₋₇ alkyl group or —(CR⁸R⁹)_(r)-E,

R⁶ and R⁷ are hydrogen atom,

R⁸ and R⁹ are independently selected from the group consisting ofhydrogen atom, fluorine atom and an optionally-substituted C₁₋₆ alkylgroup,

A is an optionally-substituted C₆₋₁₀ aryl group,

r is 1 or 2,

E is an optionally-substituted C₃₋₈ cycloalkyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 oxygen atoms as a constituent atom of the ring,or an optionally-substituted C₆₋₁₀ aryl group,

L is oxygen atom,

n is 1, and

X is hydrogen atom.

More preferably, the present compound includes a compound wherein

either of R¹ and R² is hydrogen atom, and the other is a C₁₋₆ alkylgroup (preferably methyl group),

R⁵ is an optionally-substituted C₄₋₇ alkyl group (preferably isobutylgroup, 2,2-dimethylpropyl group, 3-methylbutyl group, 3,3-dimethylbutylgroup or 2-ethylbutyl group) or —CH₂-E,

R³, R⁴, R⁶, and R⁷ are hydrogen atom,

A is an optionally-substituted C₆₋₁₀ aryl group (preferably phenyl groupor naphthyl group),

r is 1,

E is an optionally-substituted C₃₋₈ cycloalkyl group (preferablycyclopropyl group, cyclobutyl group, cyclo-pentyl group, or cyclohexylgroup) or an optionally-substituted C₆₋₁₀ aryl group (preferably phenylgroup or naphthyl group),

L is oxygen atom,

n is 1, and

X is hydrogen atom.

In another embodiment, the present compound includes preferably thefollowing compounds or pharmaceutically acceptable salts thereof:

-   1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 5-   1-{1-(cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 20-   1-{1-(cyclohexylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 21-   1-{1-(cyclohexylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 22-   1-{5-[(2-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 23-   1-{5-[(3-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 24-   1-{1-(cyclohexylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 26-   1-{1-(cyclohexylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 27-   1-{1-(cyclohexylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 29-   1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 30-   1-{1-(cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 31-   1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 33-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 34-   1-{1-(cyclohexylmethyl)-5-[(2-fluoro-5-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 35-   1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 37-   1-{1-(cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 38-   1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclohexyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 39-   1-[5-(benzyloxy)-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 4-   1-{1-(cyclopentylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 135-   1-{1-(cyclopentylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 136-   1-{1-(cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 137-   1-{5-[(2-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 138-   1-{5-[(3-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 139-   1-{1-(cyclopentylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 141-   1-{1-(cyclopentylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 142-   1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 144-   1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 145-   1-{1-(cyclopentylmethyl)-5-[(4-fluoro-2-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 146-   1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 147-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 148-   1-{1-(cyclopentylmethyl)-5-[(2-fluoro-5-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 149-   1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 150-   l-{1-(cyclopentylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 151-   1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 152-   1-[5-(benzyloxy)-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 264-   1-{5-[(3-chlorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 265-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 266-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3,3-dimethyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 267-   1-[5-(benzyloxy)-1-(3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;    Example 268-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 269-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 270-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methoxy-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 274-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 275-   1-{1-(cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 280-   l-{1-(cyclohexylmethyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;-   1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 315-   N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluoro-benzyl)oxy]-1H-pyrazol-3-yl}methanamine;    Example 283-   1-{1-(3,3-dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 284-   1-{1-(4-fluorobenzyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 218-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-fluorobenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 219-   1-{1-(4-fluorobenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;-   1-{5-[(2-fluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 228-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 230-   N-methyl-1-{1-(4-methylbenzyl)-5-[(2,4,5-trifluoro-benzyl)oxy]-1H-pyrazol-3-yl}methanamine;    Example 286-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    no Example-   1-{1-(4-methoxybenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 285-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 131-   l-{5-[(4-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 369-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methyl-propyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 256-   1-{1-(2,2-dimethylpropyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 375-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 258-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2,2-dimethyl-propyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 259-   1-{5-[(2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 381-   1-{5-[(4-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 383-   1-(5-[(4-fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)-cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanamine;    Example 446-   1-(5-[(2,5-difluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)-cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methyl-methanamine;    Example 447-   1-(5-[(5-chloro-2-fluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methyl-methanamine;    Example 448-   (−)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 474-   (+)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 475-   (−)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 476-   (+)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylethanamine;    Example 477-   1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-fluoro-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 481 and,-   1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;    Example 482.

Processes of Compound (1)

Hereinafter, processes of Compound (1) are explained.

The pyrazole compounds of the present invention can be prepared fromwell-known compounds in the art, by using the following processes orprocesses similar thereto and also optionally combining syntheticprocesses known to a person skilled in the art. The starting compoundsused herein may be well-known compounds in the art, or may be preparedby using the following processes in Examples or processes similarthereto and also optionally combining synthetic processes known to aperson skilled in the art.

Process 1

Among Compound (1), the compound wherein R² and X are hydrogen atom[i.e. Compound (A-4)] or a salt thereof can be prepared by, for example,the following process:

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, A and n are the same as defined in the above[1],

L^(a) is oxygen atom or sulfur atom,

LG is a leaving group including, for example, iodine atom, bromine atom,chlorine atom, and substituted sulfonyloxy groups such asp-toluenesulfonyloxy group, benzenesulfonyloxy group andmethanesulfonyloxy group, and

PG is a protecting group on amino group including, for example,tert-butoxycarbonyl group and benzyloxycarbonyl group.

Step (i)

Compound (A-3) or a salt thereof can be obtained by reacting Compound(A-1) or a salt thereof with Compound (A-2). The reaction can be carriedout by reacting the compounds in the presence or absence of a baseand/or a phase-transfer catalyst in a suitable inert-solvent at atemperature of about −20° C. to the boiling point of the solvent for 10minutes to 48 hours.

The base used herein includes, for example, organic bases such astriethylamine and pyridine; inorganic bases such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride, potassiumhydroxide, silver oxide and silver carbonate; and metal alkoxides suchas potassium tert-butoxide. The phase transfer catalyst used hereinincludes, for example, tetrabutylammonium hydrogen sulfate. The inertsolvent used herein includes, for example, aromatic hydrocarbons such asbenzene and toluene; ether type solvents such as diethyl ether,tetrahydrofuran (THF) and 1,4-dioxane; lower alcohols such as methanol,ethanol and isopropanol; aprotic polar solvents such asN,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) andacetonitrile; and mixed solvents thereof. Preferably, the solventincludes N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) andacetonitrile. The leaving group (LG) used herein includes preferablyhalogen atoms such as chlorine atom, bromine atom and iodine atom, andsubstituted sulfonyloxy groups such as p-toluenesulfonyloxy group,benzenesulfonyloxy group and methanesulfonyloxy group; and morepreferably halogen atoms such as chlorine atom, bromine atom and iodineatom.

Step (ii)

The protecting group (PG) on the amino group of Compound (A-3) can bedeprotected by a suitable method to give the desired Compound (A-4). Incase that the protecting group (PG) on the amino group is Boc group, thedeprotection can be carried out by treating Compound (A-3) in a suitableinert-solvent at a temperature of about −20° C. to the boiling point ofthe solvent with inorganic acids (e.g. hydrochloric acid and sulfuricacid) or organic acids (e.g. trifluoroacetic acid). The inert solventused herein includes, for example, aromatic hydrocarbons such as benzeneand toluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; lower alcohols such as methanol, ethanol andisopropanol; aprotic polar solvents such as N,N-dimethylformamide (DMF)and N-methyl-2-pyrrolidone (NMP); and mixed solvents thereof.

In case that PG is benzyloxycarbonyl group, the deprotection can becarried out by a hydrogenation reaction in a suitable inert-solvent at atemperature of about −20° C. to the boiling point of the solvent withpalladium catalysts (e.g. palladium carbon and palladium hydroxide) Theinert solvent used herein includes, for example, aromatic hydrocarbonssuch as benzene and toluene; ether type solvents such as diethyl ether,tetrahydrofuran (THF) and 1,4-dioxane; lower alcohols such as methanol,ethanol and isopropanol; aprotic polar solvents such asN,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP); and mixedsolvents thereof.

Process 2

Among Compound (1), the compound wherein L is amino group, and R² and Xare hydrogen atom [i.e. Compound (A-9)] or a salt thereof can beprepared by, for example, the following process:

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, A, PG and n are as defined above, and

R^(10a) is a C₁₋₆ alkyl group.

Step (i)

Compound (A-6) can be obtained by reacting Compound (A-1-c) or a saltthereof and Compound (A-5) or a salt thereof to form an amide bond. Inthe reaction of forming the amide bond, the carboxyl group of Compound(A-5) can be activated by acid chloride methods using thionyl chloride,oxalyl chloride and the like or mixed acid anhydride methods usingchlorocarbonates or pivaloyl chloride, or activated by condensing agentssuch as dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide (EDC or WSC) and1,1′-carbonyl-diimidazole (CDI), and then the Compound (A-5) can bereacted with Compound (A-1-c).

Step (ii)

Compound (A-7) can be obtained by reacting Compound (A-6) in a suitableinert-solvent at a temperature of about −20° C. to the boiling point ofthe solvent with a suitable reducing agent for 10 minutes to 48 hours.The suitable reducing agent used herein includes, for example, lithiumaluminum hydride and diborane. The suitable inert-solvent used hereinincludes, for example, aromatic hydrocarbons such as benzene andtoluene; and ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane.

Step (iii)

Compound (A-8) can be obtained by an alkylation reaction of Compound(A-7) in a suitable inert-solvent at a temperature of about −20° C. tothe boiling point of the solvent in the presence of a suitable base withan alkyl halide corresponding to R^(10a). The suitable inert-solventused herein includes, for example, aromatic hydrocarbons such as benzeneand toluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; lower alcohols such as methanol, ethanol andisopropanol; aprotic polar solvents such as N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidone (NMP) and acetonitrile; and mixed solventsthereof. The suitable base used herein includes, for example, inorganicbases such as potassium carbonate, sodium carbonate, cesium carbonate,sodium hydride and potassium hydride; and metal alkoxides such aspotassium tert-butoxide.

Step (iv)

The desired Compound (A-9) can be obtained by deprotecting the aminogroup of Compound (A-7) or Compound (A-8) in the same manner as in Step(ii) of Process 1.

Process 3

Among Compound (1), Compound (A-12) or a salt thereof can be prepared bythe following process:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, A, n and LG are as defined above.

Compound (A-12) or a salt thereof can be obtained by reacting Compound(A-10) or a salt thereof with Compound (A-11) or a salt thereof. Thereaction can be carried out in the presence or absence of a base and/ora phase transfer catalyst in a suitable inert-solvent at a temperatureof about −20° C. to the boiling point of the solvent for 10 minutes to48 hours. The base used herein includes, for example, organic bases suchas triethylamine and pyridine; inorganic bases such as sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride and potassiumhydroxide; and metal alkoxides such as sodium methoxide and potassiumtert-butoxide. The phase transfer catalyst used herein includes, forexample, tetrabutyl-ammonium hydrogen sulfate. The inert solvent usedherein includes, for example, aromatic hydrocarbons such as benzene andtoluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; lower alcohols such as methanol, ethanol andisopropanol; aprotic polar solvents such as N,N-dimethylformamide (DMF),N-methyl-2-pyrrolidone (NMP) and acetonitrile; and mixed solventsthereof. The leaving group (LG) used herein includes preferably halogenatoms such as chlorine atom, bromine atom and iodine atom, andsubstituted sulfonyloxy groups such as p-toluenesulfonyloxy group,benzene-sulfonyloxy group and methanesulfonyloxy group.

Process 4

Among Compound (1), the compound wherein R³, R⁴ and X are hydrogen atom[i.e. Compound (A-15)] or a salt thereof can be prepared by, forexample, the following process:

wherein

R¹, R², R⁵, R⁶, R⁷, A and n are as defined above, and

R^(a) is hydrogen atom or a C₁₋₆ alkyl group.

Step (i)

Compound (A-14) or a salt thereof can be obtained by reacting Compound(A-13) or a salt thereof and Compound (A-11) or a salt thereof tocombine them via an amide bond. In the reaction of forming the amidebond when R^(a) is hydrogen atom, the carboxyl group of Compound (A-13)can be activated by acid chloride methods using thionyl chloride, oxalylchloride and the like or mixed acid anhydride methods usingchlorocarbonates or pivaloyl chloride, or activated by condensing agentssuch as dicyclohexyl-carbodiimide (DCC),l-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC or WSC) and1,1′-carbonyl-diimidazole (CDI), and then the Compound (A-13) can bereacted with Compound (A-11). When R^(a) is a C₁₋₆ alkyl group, thereaction of forming the amide bond can be carried out by reactingCompound (A-13) and Compound (A-11) or a salt thereof in the presence orabsence of a suitable acid or base in a suitable inert-solvent or in theabsence of a solvent at a temperature of about −20° C. to the boilingpoint of the solvent for 10 minutes to 48 hours. The suitable base usedherein includes, for example, organic bases such as triethylamine andpyridine; inorganic bases such as sodium carbonate, potassium carbonate,cesium carbonate, sodium hydride and potassium hydroxide. The suitableacid used herein includes organic acids such as p-toluenesulfonic acid,acetic acid, and trifluoroacetic acid; inorganic acids such ashydrochloric acid and sulfuric acid; and Lewis acids such as aluminumchloride. The suitable inert-solvent used herein includes, for example,aromatic hydrocarbons such as benzene and toluene; ether type solventssuch as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; loweralcohols such as methanol, ethanol and isopropanol; aprotic polarsolvents such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone(NMP); and mixed solvents thereof.

Step (ii)

The step can be carried out by reacting Compound (A-14) with a suitablereducing agent in a suitable inert-solvent at a temperature of about−78° C. to the boiling point of the solvent for 10 minutes to 48 hours.The suitable reducing agent used herein includes, for example, lithiumaluminum hydride and diborane. The suitable inert-solvent used hereinincludes, for example, aromatic hydrocarbons such as benzene andtoluene; and ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane.

Process 5

Among Compound (1), the compound wherein R³ and X are hydrogen atom[i.e. Compound (A-17)] or a salt thereof can be prepared by, forexample, the following process:

wherein R¹, R², R⁴, R⁵, R⁶, R⁷, A and n are as defined above.

The desired Compound (A-17) or a salt thereof can be obtained byreacting Compound (A-16) and Compound (A-11) or a salt thereof in asuitable inert-solvent in the presence or absence of a suitable acid ata temperature of about −78° C. to the boiling point of the solvent witha suitable reducing agent under reductive amination conditions. Theinert solvent used herein includes, for example, aromatic hydrocarbonssuch as benzene and toluene; ether type solvents such as diethyl ether,tetrahydrofuran (THF) and 1,4-dioxane; lower alcohols such as methanol,ethanol and isopropanol; aprotic polar solvents such asN,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) andacetonitrile; acetic acid; water; and mixed solvents thereof. Thesuitable acid used herein includes inorganic acids such as phosphoricacid, hydrochloric acid and sulfuric acid; and organic acids such asacetic acid and trifluoroacetic acid. The reducing agent used hereinincludes, for example, sodium cyanoborohydride, sodiumtriacetoxyborohydride and sodium borohydride. Compound (A-16) andCompound (A-11) or a salt thereof may be reacted by simply mixing them,or stepwise by firstly forming an imine thereof and then reducing it.

Process 6

Among Compound (1), the compound wherein the 4-position of the pyrazolering is substituted with a halogen atom [i.e. Compound (A-20)] or a saltthereof can be prepared by, for example, the following process:

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, A, L, n and PG are as defined above, and

X^(a) is a halogen atom such as fluorine atom, chlorine atom and bromineatom.

Step (i)

Compound (A-19) can be obtained by reacting Compound (A-18) in asuitable inert-solvent at a temperature of about −78° C. to the boilingpoint of the solvent with a suitable halogenating-agent. The suitableinert-solvent used herein includes lower alcohols such as methanol,ethanol and isopropanol; and aprotic polar solvents such asN,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP). Thesuitable halogenating-agent used herein includes N-chlorosuccinimide(NCS) when X^(a) is chlorine atom, N-bromosuccinimide (NBS) and5,5-dimethyl-1,3-dibromo-hydantoin when X^(a) is bromine atom,N-iodosuccinimide (NIS) when X^(a) is iodine atom, and1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]-octanebis(tetrafluoroborate) [Selectfluor (trademark)] when X^(a) is fluorineatom.

Step (ii)

The desired Compound (A-20) can be obtained by deprotecting the aminogroup in the same manner as in Step (ii) of Process 1.

Process 7

Among Compound (1), the compound wherein the 4-position of the pyrazolering is substituted with an alkyl group [i.e. Compound (A-23)] or a saltthereof can be prepared by, for example, the following process:

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, A, L, n and PG are as defined above,

X^(b) is chlorine atom, bromine atom or iodine atom, and

X^(c) is a C₁₋₆ alkyl group optionally substituted with fluorine atomsuch as methyl group and trifluoromethyl group.

Step (i)

In case that X^(c) is methyl group, Compound (A-22) can be obtained byreacting Compound (A-21) in a suitable inert-solvent at a temperature ofabout −78° C. to the boiling point of the solvent in the presence ofzerovalent palladium catalysts [e.g. tetrakis triphenylphosphinepalladium (0), bis(dibenzylideneacetone)palladium (0) andbis(tri-tert-butylphosphine)palladium (0)] with alkyl-boronic acids(e.g. methylboronic acid), alkylaluminums (e.g. trimethylaluminum) oralkylzinc reagents (e.g. methyl zinc chloride). In case that X^(c) istrifluoromethyl group, Compound (A-22) can be obtained according to themethods disclosed in, for example, J. Fluorine. Chem. 2007, 128 (10),1318. and Eur. J. Org. Chem. 1998, (2), 335. In specific, Compound(A-21) can be obtained by reacting in the presence of monovalent cuprate[e.g. copper iodide (I)] with methyl trifluoroacetate or sodiumtrifluoroacetate.

Step (ii)

The desired Compound (A-23) can be obtained by deprotecting the aminogroup in the same manner as in Step (ii) of Process 1.

Process 8 (Introduction of a Substituent in Amino Group)

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, A, L, X and n are as defined above, and

R^(2a) is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group.

Compound (A-25) can be prepared by reacting Compound (A-24) with analkylating agent, aldehyde, ketone, carboxylic acid or estercorresponding to R^(2a) in the same manner as in Processes 3 to 5.

Process 9

Compound (A-1) in Process 1 wherein L is oxygen atom [i.e. Compound(A-1-a)] or L is sulfur atom [i.e. Compound (A-1-b)] can be prepared bythe following process:

wherein

R¹, R³, R⁴, R⁵ and PG are as defined above,

M is alkali metals such as sodium and potassium, or alkaline earthmetals such as magnesium and calcium, and

R is a C₁₋₆ alkyl group.

Steps (i) to (ii)

Compound (B-3) can be prepared from Compound (B-1) and Compound (B-2) ora salt thereof in the same manner as disclosed in, for example,Tetrahedron, 60(2004), 1731-1848). In specific, Compound (B-3) can beobtained by activating Compound (B-1) in a suitable inert-solvent at atemperature of about −20° C. to 30° C. with carbonyldiimidazole (CDI);and then reacting the Compound (B-1) in the presence of a suitable acidor base at a temperature of about −20° C. to the boiling point of thesolvent with Compound (B-2). The suitable inert solvent used hereinincludes, for example, aromatic hydrocarbons such as benzene andtoluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; and mixed solvents thereof. The suitable acidused herein includes magnesium chloride. Compound (A-1-a) can beprepared by reacting Compound (B-3) and Compound (B-4) in the presenceof a suitable acid or base in a suitable inert solvent or in the absenceof a solvent at a temperature of about −20° C. to the boiling point ofthe solvent for 10 minutes to 48 hours. The suitable base used hereinincludes, for example, organic bases such as triethylamine and pyridine;metal alkoxides such as potassium tert-butoxide; and inorganic basessuch as sodium carbonate, potassium carbonate and cesium carbonate. Thesuitable acid used herein includes organic acids such asp-toluenesulfonic acid, methanesulfonic acid, acetic acid andtrifluoroacetic acid; and inorganic acids such as hydrochloric acid,sulfuric acid and phosphoric acid. The suitable inert solvent usedherein includes, for example, aromatic hydrocarbons such as benzene andtoluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; lower alcohols such as methanol, ethanol andisopropanol; aprotic polar solvents such as N,N-dimethylformamide (DMF)and N-methyl-2-pyrrolidone (NMP); and mixed solvents thereof.

Step (iii)

Compound (A-1-b) can be prepared by reacting Compound (A-1-a) in asuitable inert-solvent or in the absence of a solvent at a temperatureof about −20° C. to the boiling point of the solvent with Lawesson'sreagent. The suitable inert-solvent used herein includes, for example,aromatic hydrocarbons such as benzene and toluene; and ether typesolvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane.

Process 10

On the basis of the process disclosed in Journal of HeterocyclicChemistry, 2009, 39, Compound (A-1-c) in Process 2 can be prepared bythe following process:

wherein R¹, R³, R⁴, R⁵, PG and R are as defined above.

Step (i)

Compound (B-6) can be obtained by reacting Compound (B-5) in a suitableinert-solvent at a temperature of about −78° C. to the boiling point ofthe solvent with an anion generated by reacting acetonitrile with asuitable base. The suitable inert-solvent used herein includes, forexample, aromatic hydrocarbons such as benzene and toluene; and ethertype solvents such as diethyl ether, tetra-hydrofuran (THF) and1,4-dioxane. The suitable base used herein includes, for example,inorganic bases such as sodium hydride and potassium hydroxide, andmetal alkoxides such as sodium methoxide and potassium tert-butoxide.

Step (ii)

Compound (A-1-c) can be obtained by reacting Compound (B-6) and Compound(B-4) in the same manner as in Step (ii) of Process 9.

Process 11

Compound (A-10), Compound (A-13) and Compound (A-16) in Processes 3 to 5can be prepared by the following process:

wherein

R³, R⁴, R⁵, R⁶, R⁷, LG, n, A and R^(a) are as defined above, and

M¹ is hydrogen atom, an alkali metal such as sodium and potassium, or analkaline earth metal such as magnesium and calcium.

Step (i)

On the basis of the process disclosed in Bioorganic & MedicinalChemistry Letters, 17 (2007), 5567, Compound (B-8) can be prepared byreacting Compound (B-7) in the presence of a suitable acid or base, in asuitable inert-solvent or in the absence of a solvent, at a temperatureof about −20° C. to the boiling point of the solvent with Compound (B-4)for 10 minutes to 48 hours. The suitable base used herein includes, forexample, amines such as triethylamine and pyridine; and inorganic basessuch as sodium carbonate, potassium carbonate and cesium carbonate. Thesuitable acid used herein includes organic acids such asp-toluenesulfonic acid, methanesulfonic acid, acetic acid andtrifluoroacetic acid; and inorganic acids such as hydrochloric acid,sulfuric acid and phosphoric acid. The suitable inert-solvent usedherein includes, for example, aromatic hydrocarbons such as benzene andtoluene; ether type solvents such as diethyl ether, tetrahydrofuran(THF) and 1,4-dioxane; lower alcohols such as methanol, ethanol andisopropanol; aprotic polar solvents such as N,N-dimethylformamide (DMF)and N-methyl-2-pyrrolidone (NMP); and mixed solvents thereof.

Step (ii)

Compound (A-13) can be obtained by reacting Compound (B-8) and Compound(A-2) in the same manner as in Step (i) of Process 1.

Steps (iii) to (vii)

Compound (A-13) can be, if necessary, converted to Compound (A-10) orCompound (A-16) by general processes typically used in the art (see, forexample, Comprehensive Organic Transformations, R. C. Larock, 1989).

Process 12

Among Compound (1), Compound (A-12-a) or a salt thereof can be preparedby the following process:

wherein

R¹, R³, R⁴, R⁵, R⁶, R⁷, LG, n, and A are as defined above, and

PG¹ is a protecting group on the amino group such as tert-butoxycarbonylgroup and benzyloxycarbonyl group, or the two PG¹ groups attached to thesame nitrogen atom may be combined with the nitrogen atom to form a ringsuch as phthalic imide and succinimide.

Step (i)

Compound (A-3-a) or Compound (A-3-b), or a salt thereof can be obtainedby reacting Compound (A-10) or a salt thereof with Compound (B-10-a) orCompound (B-10-b), or a salt thereof. The reaction can be carried out inthe presence or absence of a base and/or phase transfer catalyst, in asuitable inert-solvent, at a temperature of about −20° C. to the boilingpoint of the solvent for 10 minutes to 48 hours. The base used hereinincludes, for example, organic bases such as triethylamine and pyridine;inorganic bases such as sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydroxide, potassium hydroxide, sodium hydride andpotassium hydroxide; and metal alkoxides such as sodium methoxide andpotassium tert-butoxide. The phase transfer catalyst used hereinincludes, for example, tetrabutylammonium hydrogen sulfate. The inertsolvent used herein includes, for example, aromatic hydrocarbons such asbenzene and toluene; ether type solvents such as diethyl ether,tetrahydrofuran (THF) and 1,4-dioxane; lower alcohols such as methanol,ethanol and isopropanol; aprotic polar solvents such asN,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) andacetonitrile; and mixed solvents thereof. The leaving group (LG) usedherein includes preferably halogen atoms such as chlorine atom, bromineatom and iodine atom; and substituted sulfonyloxy groups such asp-toluenesulfonyloxy group, benzenesulfonyloxy group andmethanesulfonyloxy group.

Step (ii)

The desired Compound (A-12-a) can be obtained by deprotecting the aminogroup in the same manner as in Step (ii) of Process 1. In case that thetwo PG¹ groups attached to the same nitrogen atom are combined with thenitrogen atom to form a ring of phthalic imide or succinimide, the stepcan be carried out by reacting the compound with an amino compound (e.g.hydrazine monohydrate and methylamine) in a suitable inert solvent or inthe absence of a solvent at a temperature of about −20° C. to theboiling point of the solvent for 10 minutes to 48 hours. The inertsolvent used herein includes, for example, aromatic hydrocarbons such asbenzene and toluene; ether type solvents such as diethyl ether,tetrahydrofuran (THF) and 1,4-dioxane; lower alcohols such as methanol,ethanol and isopropanol; and mixed solvents thereof.

Unless otherwise noted, the starting materials and reagents used in theabove processes are commercially available or can be prepared fromwell-known compounds by well-known methods. Furthermore, the functionalgroup of the above-shown Compound (1) may be modified to prepare adifferent type of Compound (1). The modification of the functional groupcan be carried out according to general methods typically used in theart (e.g. see, Comprehensive Organic Transformations, R. C. Larock,1989).

Among the above-shown processes, in case that functional groups otherthan the reactive site could react under the given reaction-condition orare not suitable to carry out the given process, the desired compoundcan be obtained by firstly protecting the functional groups with asuitable protecting group, and then carrying out the reaction anddeprotecting the protecting group. The protecting group used hereinincludes typical protecting groups disclosed in, for example, ProtectiveGroups in Organic Synthesis, T. W. Greene, John Wiley & Sons Inc., 1981.In specific, protecting groups on amine include, for example,ethoxycarbonyl, tert-butoxycarbonyl, benzyloxy-carbonyl, acetyl, benzoyland benzyl. Protecting groups on hydroxy group include, for example,trialkylsilyl, acetyl, benzoyl and benzyl. Protecting groups of ketoneinclude, for example, dimethylacetal, 1,3-dioxane, 1,3-dioxolane,S,S′-dimethyldithioacetal, 1,3-dithiane, and oxime.

The protecting groups can be induced and deprotected according tomethods typically-used in synthetic organic chemistry (e.g. see, theabove-cited Protective Groups in Organic Synthesis) and other similarmethods.

The intermediates and desired compounds in the above-shown processes canbe isolated and purified according to purification methods which aretypically used in synthetic organic chemistry such as neutralization,filtration, extraction, washing, drying, concentration,recrystallization, various chromatographies, and the like. Furthermore,the intermediates can be used for the subsequent reaction withoutspecific purification.

Compound (1) or a pharmaceutically acceptable salt thereof may includetautomers thereof. The tautomers include, for example, the followingformula:

In addition to the tautomers, the present invention also includes otherpossible isomers such as optical isomers, stereoisomers, regioisomersand rotamers, and mixtures thereof. For example, in case that opticalisomers of Compound (1) exist, each optical isomer thereof is alsoincluded in Compound (1). The isomers can be isolated and purified bywell-known synthetic and resolving methods such as chromatography andrecrystallization.

Each optical isomer of Compound (1) can be resolved according to opticalresolution methods which are well-known to a person skilled in the art.For example, according to typical methods, the resolution can be carriedout by forming diastereomeric salts with an optically active acid,resolving the diastereomeric salts into two types, and then convertingthem into a free base. The optically active acid used herein includes,for example, monocarboxylic acids such as mandelic acid,N-benzyloxyalanine and lactic acid; dicarboxylic acids such as tartaricacid, o-diisopropylidene tartaric acid and malic acid; and sulfonicacids such as camphorsulfonic acid and bromo camphorsulfonic acid. Thetemperature used herein to form salts includes room temperature to theboiling point of the solvent.

Furthermore, Compound (1) includes compounds labeled with isotopes suchas ³H, ¹⁴C, ³⁵S and ¹²⁵I, and also compounds wherein ¹H is substitutedwith deuterium, i.e. ²H (D).

The pharmaceutically acceptable salts of Compound (1) are typically-usednontoxic salts including, for example, acid addition salts such asorganic acid salts (e.g. acetate, propionate, trifluoroacetate, maleate,fumarate, citrate, succinate, tartrate, methanesulfonate,benzene-sulfonate, formate and toluenesulfonate) and inorganic acidsalts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrateand phosphate); salts with amino acids such as arginine acid, asparticacid and glutamic acid; metal salts such as alkali metal salts (e.g.sodium salt and potassium salt) and alkaline earth metal salts (e.g.calcium salt and magnesium salt); ammonium salts; and organic base salts(e.g. trimethylamine salt, triethylamine salt, pyridine salt, picolinesalt, dicyclohexylamine salt and N,N′-dibenzylethylenediamine salt).

In case that Compound (1) is given in the form of a pharmaceuticallyacceptable salt, the pharmaceutically acceptable salt of Compound (1)can be obtained by directly purifying the product. On the other hand, incase that Compound (1) is given in a free form, the pharmaceuticallyacceptable salt of Compound (1) can be obtained by a typical method,i.e. dissolving or suspending the product in a suitable organic solvent,and then adding an acid or base thereto. For example, the salt can beformed by mixing the product with a pharmaceutically acceptable acid oralkali in a solvent such as water, methanol, ethanol, acetone, and thelike.

Furthermore, Compound (1) and a pharmaceutically acceptable salt thereofmay exist as a hydrate containing water or a solvate containing varioussolvents such as ethanol, and thus the hydrate and solvate thereof arealso included in the present invention.

In case that Compound (1) or a pharmaceutically acceptable salt thereofis given as a crystal, crystalline polymorphisms may exist in thecrystal, and thus the crystalline polymorphisms are also included in thepresent invention.

The present pyrazole-compound and a pharmaceutically acceptable saltthereof have human serotonin reuptake inhibitory action and 5-HT_(2C)antagonistic action, in particular, inverse agonistic action. Thus, thecompound and salt are useful as a medicament for treating diseasesmediated by serotonin nervous system or preventing a relapse thereof.The diseases mediated by serotonin nervous system include, for example,depression and anxiety. Depression is included in mood disorderaccording to the classification of psychiatric disease. The mooddisorder mainly includes depressive disorder and bipolar disorder. Inmore detail, a general depression includes, for example, (i) depressivedisorders such as major depressive disorder, dysthymic disorder, anddepressive disorders not otherwise specified, (ii) depression, and (iii)seasonal affective disorder. The present compound and salt thereof areuseful as a medicament for treating the above-mentioned diseases orpreventing a relapse thereof. Furthermore, the present compound and saltthereof are also useful as a medicament for treating (iv) majordepressive episode in bipolar disorder, or preventing a relapse thereof.On the other hand, anxiety (anxiety disorder) mainly includes anxietydisorder and phobia. The present compound and salt thereof are useful asa medicament for treating anxiety (anxiety disorder) such as (v) panicdisorder, obsessive-compulsive disorder, posttraumatic stress disorder,acute stress disorder, generalized anxiety disorder and anxiety disorderdue to a general medical condition, (vi) anxiety disorder comprisingsubstance-induced anxiety disorder, (vii) agoraphobia, (viii) socialphobia, (ix) avoidant personality disorder, and (x) psychophysiologicaldisorder, or preventing a relapse thereof. Furthermore, the presentcompound and salt thereof are also useful for treating symptoms ofdepression and anxiety associated with other diseases such asschizophrenia and dementia, or preventing a relapse thereof. Moreover,the present compound and salt thereof are also useful for treatingmemory impairments such as dementia, amnesia and age-related memoryimpairments; eating behavior disorder including neural anorexia andneural starvation; obesity; sleep disorder; schizophrenia; addiction todrugs such as alcohol, tobacco, nicotine, narcotic, psychostimulant andpsychotropic drug; cluster headache; migraine; pain; Alzheimer'sdisease; chronic paroxysmal hemicrania; headache associated withvascular disorder; Parkinson's disease including dementia, depressionand anxiety in Parkinson's disease, neuroleptic-induced Parkinson'ssyndrome, and tardive dyskinesia; endocrine abnormality such ashyperprolactinemia; vasospasm (in particular, in cerebrovascularsystem); hypertension; gastrointestinal disorder associated withmotility and secretory change; and sexual dysfunction such as precociousejaculation, or preventing a relapse thereof.

The dose of the present pyrazole-compound and a pharmaceuticallyacceptable salt thereof may vary depending on the age and condition ofpatients; and in general, when the patients are human beings, 0.1 mg toabout 1,000 mg, preferably 1 mg to about 100 mg can be administered as adaily dose per the individual patient. The administration may be once orseveral times a day, and each administration may include 1, 2 or 3doses.

In case that the present pyrazole-compound and a pharmaceuticallyacceptable salt thereof is used for treatment, they can be administeredorally or parenterally [e.g. intravenously, subcutaneously,intramuscularly, intrathecally, topically, transrectally,percutaneously, nasally and pulmonarily (i.e. by lung)] as apharmaceutical composition. Oral dosage forms include, for example,tablets, capsules, pills, granules, fine granules, powders, solutions,syrups and suspensions; and parenteral dosage forms include, forexample, aqueous injections, non aqueous injections, suppositories,nasal preparations, transdermal preparations such as lotions, emulsion,ointments, creams, jellies, gels, adhesive skin patches (e.g. tapes,transdermal patches and poultices), topical powders, and the like. Theseformulations can be formulated according to conventionally well-knowntechniques, and they may comprise nontoxic and inactive carriers orexcipients which are typically used in the field of formulation.

The pharmaceutically acceptable carriers used for formulation includesubstances typically used in the field of formulation which react withneither Compound (1) nor a pharmaceutically acceptable salt thereof. Inspecific, the pharmaceutical composition containing Compound (1) or apharmaceutically acceptable salt thereof may further comprise carriersused for formulation such as excipients, binders, lubricants,stabilizers, disintegrants, buffers, solubilizers, tonicity agents, pHadjusters, surfactants, emulsifying agents, suspending agents,dispersants, suspension stabilizers, thickeners, viscosity modifiers,gelling agents, soothing agents, preservatives, plasticizers,transdermal-absorption promoters, antioxidants, humectants, antiseptics,flavors, and the like. Furthermore, the pharmaceutical composition mayoptionally comprise a mixture of two or more of the above-listedcarriers used for formulation.

Solid formulations such as tablets can be formulated by mixing theactive ingredient with, for example, pharmaceutically acceptablecarriers or excipients typically used in the art (e.g. lactose, sucroseand corn starch), binders (e.g. crystalline cellulose,hydroxy-propylcellulose, polyvinylpyrrolidone and hydroxypropylmethylcellulose), disintegrants (e.g. carboxymethyl-cellulose sodium andsodium carboxymethyl starch), lubricants (e.g. stearic acid andmagnesium stearate), and preservatives.

When administering parenterally, the active ingredient is dissolved orsuspended in physiologically acceptable carriers such as water, saline,oil and aqueous glucose solution; and if necessary, adjuvants such asemulsifying agents, stabilizing agents, salts for regulating osmoticpressure and/or buffers may be added thereto.

In case that the present pyrazole-compound and a pharmaceuticallyacceptable salt thereof are applied to pharmaceutical use as mentionedabove, they are generally administered in the form of a formulationmixed with the carriers used for formulation. Such a formulation can beprepared according to typical methods. For example, the pharmaceuticalcomposition of the present invention may contain the presentpyrazole-compound and a pharmaceutically acceptable salt thereof as anactive ingredient in an amount of 0.05 wt % to 99 wt %, preferably 0.05wt % to 80 wt %, more preferably 0.1 wt % to 70 wt %, even morepreferably 0.1 wt % to 50 wt %. The formulation may comprise otheringredients which are efficacious for the treatment.

The formulation of the present compound may be, for example, tabletswhich can be formulated by mixing 20 mg of the compound of Example 1,100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesiumstearate, and then compressing the mixture.

For the purpose of enhancing efficacy, the present pyrazole-compound anda pharmaceutically acceptable salt thereof may be used in combinationwith medicaments (i.e. combined medicaments) such as antidepressants,anxiolytic drugs, antipsychotic drugs, dopamine receptor agonists,anti-Parkinson drugs, antiepileptic drugs, antiseizure drugs, analgesicdrugs, hormone preparations, therapeutic drugs for migraine, adrenergicP receptor antagonists, therapeutic drugs for dementia and therapeuticdrugs for mood disorder. Furthermore, for the purpose of reducing sideeffects, the present pyrazole-compound and a pharmaceutically acceptablesalt thereof may be used in combination with medicaments (i.e. combinedmedicaments) such as antiemetic drugs, sleep-inducing drugs andanticonvulsants. The timing of administration of the present compoundand the additional medicament is not limited, and thus they can beadministered simultaneously or sequentially to the subject. Furthermore,the present compound and the additional medicament can be used as a drugcombination. The dose of the combined medicament may vary, and can bedetermined on the basis of the amount used in clinical practice. Theratio of the present compound and combined medicament can be determinedon the basis of, for example, the subject, administration route,disease, symptom, or combination of the drug. For example, when thesubject is human beings, 0.01 to 1000 parts by volume of the combinedmedicament per part by volume of the present compound may be used.

EXAMPLE

Hereinafter, the present invention is illustrated in more detail byReference examples, Examples and Tests, but the technical scope of thepresent invention should not be limited thereto. In addition, thecompound names shown in the Reference Examples and Examples below do notnecessarily follow the IUPAC nomenclature system.

The following abbreviations may be used in the Reference examples andExamples.

Me: Methyl

Et: Ethyl

n-Bu: Normal butyl

n-Pent: Normal pentyl

n-Hex: Normal hexyl

n-Hep: Normal heptyl

Boc: tert-Butoxycarbonyl

DMSO: Dimethylsulfoxide

THF: Tetrahydrofuran

DMF: N,N-dimethylformamide

CDI: 1,1′-Carbonyldiimidazole

Ms: Methanesulfonyl

Bn: Benzyl

TFA: Trifluoroacetic acid

DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene

PTLC: Preparative thin layer chromatography

Obs MS [M+1]: Observed protonated-molecule

Compounds were identified by proton nuclear magnetic resonance spectra(¹H-NMR spectra) and mass spectra (LC-MS). In the LC-MS analysis, themass spectra of molecules protonated by electro spray ionization wereobserved.

Preparation of Pyrazol Compounds: Reference Example 1 tert-Butyl{[1-(cyclopentylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

Step (i)

To a solution of Compound (Ia) (142 g, 0.75 mol) in THF (750 mL) wasadded CDI (134 g, 0.83 mol) in small portions at 21° C. to 23° C. over15 minutes. The reaction mixture was stirred at room temperature for 1.5hours, and then magnesium chloride (92.8 g, 0.98 mol) and potassiumethyl malonate (166 g, 0.98 mmol) were added thereto. The reactionmixture was stirred at 50° C. for 2 hours, cooled to room temperature,and water (1.5 L) was added thereto with cooling the reaction to keepthe internal temperature below 25° C. The solution was extracted withtoluene (2 L), and the combined organic layers were subsequently washedwith 5% K₂CO₃ (1.5 L), water (×2, both 1.5 L), 5% KHSO₄ (×2, 1.5 L and1.0 L) and water (1.5 L). The organic layer was dried over anhydrousMgSO₄, and the solvent was evaporated under reduced pressure to giveCompound (IIa) (183 g, 91%) as a yellow-brown oil.

Step (ii)

A solution of (cyclopentylmethyl) hydrazine dihydro-chloride (82.1 g,0.43 mol) and triethylamine (108 g, 1.1 mol) in ethanol (855 mL) wasstirred at 55° C. After the solution was homogeneous, the Compound (IIa)(108.5 g, 0.41 mol) was added thereto. The reaction mixture was stirredat 65° C. for about 1 hour and cooled to room temperature. To themixture were added 5% KHSO₄ (584 g) and then water (876 mL). The ethanolwas evaporated under reduced pressure until the total weight was 1567 g.The concentrated residue was extracted with ethyl acetate (×2, 1.4 L and0.95 L), the combined organic layers were dried over anhydrous MgSO₄,and the solvent was evaporated under reduced pressure. To theconcentrated residue was added ethyl acetate (332 mL), and the mixturewas heated. After the solid was dissolved, the solution was cooled to45° C. and seed crystals of Compound (IIIa) were added thereto. Themixture was stirred at 43° C. to 45° C. (internal temperature) for 1hour, and n-hexane (332 mL) was added dropwise thereto over 45 minuteswith keeping the internal temperature at 43° C. to 45° C. The mixturewas stirred at the same condition for 1 hour, stirred with slowlycooling to 10° C. over 3 hours, and then stirred at 4° C. to 10° C.(internal temperature) for 1 hour. The resulting precipitate wascollected by filtration and washed twice with a mixture of cooledn-hexane/ethyl acetate (1:1) (116 mL). The obtained powder was driedunder reduced pressure to give Compound (IIIa) (92.5 g, 70%) as a whitesolid.

¹H-NMR (300 MHz, CDCl₃) δ: 1.20-1.75 (8H, m), 1.46 (9H, s), 2.23-2.35(1H, m), 2.84 (3H, br s), 3.20 (2H, s), 3.55 (2H, d, J=7.5 Hz), 4.10(2H, br s).

The following compounds of Reference Examples 2 to 30 were prepared inthe same manner as in Reference Example 1.

Reference Example 2 tert-Butyl{[1-(cyclopropylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.29-0.38 (2H, m), 0.49-0.55 (2H, m),1.08-1.29 (1H, m), 1.47 (9H, s), 2.88 (3H, br s), 3.23 (2H, s), 3.51(2H, d, J=7.0 Hz), 4.14 (2H, br s).

Reference Example 3 tert-Butyl{[1-(cyclobutylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 1.72-1.94 (4H, m), 1.98-2.09(2H, m), 2.62-2.77 (1H, m), 2.86 (3H, br s), 3.21 (2H, s), 3.67 (2H, d,J=7.3 Hz), 4.11 (2H, br s).

Reference Example 4 tert-Butyl{[1-(cyclohexylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.87-1.06 (2H, m), 1.10-1.31 (4H, m), 1.47(9H, s), 1.61-1.81 (5H, m), 3.12 (3H, s), 3.23 (2H, s), 3.48 (2H, d,J=7.0 Hz), 4.11 (2H, s).

Reference Example 5 tert-Butylmethyl{[5-oxo-1-(tetrahydro-2H-pyran-2-yl-methyl)-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.21-1.72 (14H, m), 1.79-1.93 (1H, m), 2.86(3H, brs), 3.24 (1H, s), 3.32-3.44 (1H, m), 3.52-3.67 (2H, m), 3.70-3.83(1H, m), 3.94-4.31 (4H, m).

Reference Example 6 tert-Butyl{[1-(l-cyclopentylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.10-1.23 (3H, m), 1.25 (3H, d, J=6.6 Hz),1.37-1.66 (13H, m), 1.72-1.83 (1H, m), 2.16 (1H, tdd, J=16.9, 7.7, 2.1Hz), 2.83 (3H, br s), 3.20 (2H, s), 3.90-4.00 (1H, m), 4.03-4.17 (2H,m).

Reference Example 7 tert-Butyl{[1-(1-cyclohexylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.88-1.06 (2H, m), 1.07-1.23 (4H, m), 1.26(3H, d, J=6.8 Hz), 1.47 (9H, s), 1.52-1.88 (5H, m), 2.86 (3H, s), 3.23(2H, s), 3.89-4.00 (1H, m), 4.11 (2H, s).

Reference Example 8 tert-Butyl{[1-(1-cyclohexylpropyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.78 (3H, t, J=7.3 Hz), 0.88-1.26 (5H, m),1.47 (9H, s), 1.55-1.88 (8H), 2.85 (3H, s), 3.26 (2H, s), 3.73 (1H, m),4.12 (2H, s).

Reference Example 9 tert-Butyl{[1-(bicyclo[2.2.1]hept-2-ylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.07-1.20 (4H, m), 1.31-1.55 (13H, m),1.87-1.96 (1H, m), 2.03-2.07 (1H, m), 2.22-2.26 (1H, m), 2.87 (3H, brs), 3.22 (2H, br s), 3.43 (2H, ddd, J=36.3, 13.8, 7.8 Hz), 4.07-4.16(2H, m).

Reference Example 10 tert-Butylmethyl{[1-(7-oxabicyclo[2.2.1]hept-2-ylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.34-1.74 (15H, m), 2.13-2.22 (1H, m), 2.88(3H, br s), 3.23 (2H, s), 3.53 (2H, br ddd, J=38.7, 13.8, 7.5 Hz), 4.11(2H, br s), 4.41 (1H, d, J=4.4 Hz), 4.58 (1H, t, J=4.6 Hz).

Reference Example 11 tert-Butylmethyl{[1-(2-oxabicyclo[2.2.2]oct-3-ylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.43-1.76 (15H, m), 1.94-2.04 (3H, m), 2.86(3H, br s), 3.23 (2H, br s), 3.64-3.92 (3H, m), 4.02-4.24 (3H, m).

Reference Example 12 tert-Butyl({1-[(4,4-difluorocyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.39 (2H, m), 1.47 (9H, s), 1.59-1.90 (5H,m), 2.09 (2H, m), 2.87 (3H, s), 3.24 (2H, s), 3.56 (2H, d, J=6.8 Hz),4.11 (2H, br s).

Reference Example 13 tert-Butyl({1-[(l-fluorocyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)methylcarbamate

¹H-NMR (400 MHz, CDCl₃) δ: 1.15-1.69 (17H, m), 1.74-1.88 (2H, m), 2.86(3H, brs), 3.25 (2H, s), 3.79 (2H, d, J=19.5 Hz), 4.13 (2H, brs).

Reference Example 14 tert-Butyl{[1-(2-cyclopentylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.12 (2H, m), 1.47 (9H, s), 1.47-1.88 (9H,m), 2.87 (3H, s), 3.22 (2H, s), 3.65 (2H, t, J=7.2 Hz), 4.12 (2H, s).

Reference Example 15 tert-Butyl[(1-butyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-methyl] methylcarbamate

¹H-NMR (400 MHz, CDCl₃) δ: 0.94 (3H, t, J=7.3 Hz), 1.34 (2H, m), 1.47(9H, s), 1.66 (2H, quin, J=7.3 Hz), 2.87 (3H, s), 3.22 (2H, s), 3.64(2H, t, J=7.2 Hz), 4.12 (2H, s).

Reference Example 16 tert-Butylmethyl[(5-oxo-1-pentyl-4,5-dihydro-1H-pyrazol-3-yl)methyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.89 (3H, t, J=7.0 Hz), 1.24-1.40 (4H, m),1.47 (9H, s), 1.67 (2H, quin, J=7.2 Hz), 2.87 (3H, s), 3.22 (2H, s),3.63 (2H, t, J=7.2 Hz), 4.12 (2H, s).

Reference Example 17 tert-Butyl[(1-hexyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-methyl] methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.88 (3H, t, J=6.7 Hz), 1.22-1.36 (6H, m),1.47 (9H, s), 1.61-1.73 (2H, m), 2.87 (3H, br s), 3.22 (2H, s), 3.63(2H, t, J=7.2 Hz), 4.07-4.17 (2H, m).

Reference Example 18 tert-Butyl[(1-heptyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)-methyl]methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.88 (3H, t, J=7.2 Hz), 1.24-1.35 (8H, m),1.47 (9H, s), 1.66 (2H, m), 2.87 (3H, s), 3.22 (2H, s), 3.63 (2H, t,J=7.2 Hz), 4.12 (2H, s).

Reference Example 19 tert-Butylmethyl{[5-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.83 (6H, t, J=7.3 Hz), 1.47 (9H, s), 1.68(4H, m), 2.86 (3H, br s), 3.27 (2H, s), 3.91 (1H, tt, J=8.8, 4.0 Hz),4.12 (2H, br s).

Reference Example 20 tert-Butylmethyl{[1-(2-methylpropyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.92 (6H, d, J=6.8 Hz), 1.47 (9H, s),2.03-2.12 (1H, m), 2.87 (3H, br s), 3.24 (2H, s), 3.46 (2H, d, J=7.2Hz), 4.07-4.16 (2H, m).

Reference Example 21 tert-Butyl{[1-(2,2-dimethylpropyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (400 MHz, CDCl₃) δ: 0.96 (9H, s), 1.47 (9H, s), 2.87 (3H, br s),3.22 (2H, s), 3.45 (2H, s), 4.07-4.14 (2H, m).

Reference Example 22 tert-Butyl{[1-(3,3-dimethylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.96 (9H, s), 1.47 (9H, s), 1.56-1.61 (2H,m), 2.87 (3H, br s), 3.20 (2H, br s), 3.63-3.69 (2H, m), 4.12 (2H, brs).

Reference Example 23 tert-Butyl{[1-(2-ethylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.89 (6H, t, J=7.5 Hz), 1.26-1.38 (4H, m),1.47 (9H, s), 1.67-1.77 (1H, m), 2.86 (3H, br s), 3.22 (2H, br s), 3.54(2H, d, J=7.0 Hz), 4.11 (2H, br s).

Reference Example 24 tert-Butylmethyl{[1-(3-methylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.94 (6H, d, J=6.1 Hz), 1.47 (9H, s),1.53-1.68 (3H, m), 2.87 (3H, br s), 3.22 (2H, br s), 3.66 (2H, br t,J=7.2 Hz), 4.11 (2H, br s).

Reference Example 25 tert-Butylmethyl{[5-oxo-1-(4,4,4-trifluorobutyl)-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 1.90-2.23 (4H, m), 2.88 (3H,s), 3.25 (2H, s), 3.72 (2H, t, J=6.8 Hz), 4.12 (2H, s).

Reference Example 26 tert-Butyl{[l-(3-methoxy-3-methylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.20 (6H, s), 1.47 (9H, s), 1.82-1.88 (2H,m), 2.86 (3H, br s), 3.17-3.26 (5H, m), 3.68-3.77 (2H, m), 4.08-4.14(2H, m).

Reference Example 27 tert-Butylmethyl({1-[(l-methylcyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.94 (3H, s), 1.24-1.56 (19H, m), 2.87 (3H,s), 3.21 (2H, s), 3.48 (2H, s), 4.11 (2H, s).

Reference Example 28 tert-Butylmethyl({1-[(2-methylcyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.93 (3H, d, J=7.2 Hz), 1.14-1.45 (7H, m),1.47 (9H, s), 1.65 (1H, m), 1.81 (1H, m), 2.01 (1H, m), 2.86 (3H, s),3.22 (2H, s), 3.49 (1H, dd, J=12.3, 5.9 Hz), 3.57 (1H, dd, J=12.3, 6.9Hz), 4.11 (2H, s).

Reference Example 29 tert-Butylmethyl({1-[(3-methylcyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.63 (1H, m), 0.74-0.95 (5H, m), 1.13-1.42(2H, m), 1.47 (9H, s), 1.55-1.85 (5H, m), 2.87 (3H, s), 3.23 (2H, s),3.47 (2H, d, J=7.2 Hz), 4.11 (2H, br s).

Reference Example 30 tert-Butylmethyl({1-[(4-methylcyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.92 (3H, d, J=7.0 Hz), 1.24-1.73 (18H, m),1.97 (1H, m), 2.86 (3H, s), 3.23 (2H, s), 3.59 (2H, d, J=7.7 Hz), 4.12(2H, br s).

Reference Example 31 tert-Butyl{1-[1-(cyclopentylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}methylcarbamate

The title compound was prepared in the same manner as in ReferenceExample 1 except that N-tert-butoxycarbonyl-N-methylalanine was used.

¹H-NMR (300 MHz, CDCl₃) δ: 1.14-1.87 (20H, m), 2.32 (1H, m), 2.68 (3H,s), 3.17 (2H, m), 3.58 (2H, d, J=7.5 Hz), 5.11 (1H, br s).

The compounds of Reference Examples 32 to 35 were prepared in the samemanner as in Reference Example 31.

Reference Example 32 tert-Butyl{1-[1-(cyclohexylmethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.97 (2H, m), 1.20 (4H, m), 1.39 (3H, d, 7.0Hz), 1.47 (9H, s), 1.68 (5H, m), 2.69 (3H, s), 3.17 (2H, m), 3.45 (1H,dd, J=14.0, 7.1 Hz), 3.51 (1H, dd, J=14.0, 7.4 Hz), 5.09 (1H, br s).

Reference Example 33 tert-Butyl{1-[l-(2-cyclopentylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.12 (2H, m), 1.40 (3H, d, J=7.0 HZ),1.47-1.87 (18H, m), 2.69 (3H, s), 3.16 (2H, m), 3.62 (1H, dt, J=14.3,7.1 Hz), 3.68 (1H, dt, J=14.3, 7.1 Hz), 4.95 (1H, br s).

Reference Example 34 tert-Butyl{1-[1-(2-cyclohexylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.81-1.81 (25H, m), 2.68 (3H, s), 3.16 (2H,m), 3.64 (1H, dt, J=14.5, 7.2 Hz), 3.70 (1H, dt, J=14.5, 7.5 Hz), 4.96(1H, br s).

Reference Example 35 tert-Butyl{1-[1-(2-ethylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.87 (6H, t, J=7.4 Hz), 1.29 (4H, m), 1.36(3H, d, J=7.2 Hz), 1.45 (9H, s), 1.71 (1H, m), 2.66 (3H, s), 3.14 (2H,m), 3.53 (2H, d, J=7.0 Hz), 5.05 (1H, br s).

Reference Example 36 tert-Butyl[(1-benzyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl)methyl]methylcarbamate

Step (i)

To a solution of Compound (Ib) (1.32 g, 6.3 mmol) in a mixture of aceticacid (13 mL) and toluene (6.3 mL) was added a solution of Compound (IIb)(1.00 g, 6.3 mmol) in water (6.3 mL). The reaction mixture was stirredat 80° C. for 4 hours, at 120° C. for 3 hours, and then at 130° C. for 3hours. The solvent was evaporated under reduced pressure and water (3mL) was added to the concentrated residue. The resulting solid wascollected by filtration and toluene (5 mL) was added thereto. Themixture was heated under reflux for 1 hour, slowly cooled to 0° C., andstirred at 0° C. for 1 hour. The solid was collected by filtration anddried under reduced pressure to give Compound (IIIb) (919 mg, 59%).

Steps (ii) to (iii)

To a solution of the Compound (IIIb) (710 mg, 2.9 mmol) and K₂CO₃ (418mg, 3.0 mmol) in dimethylformamide (8.6 mL) was added benzyl bromide(360 μL, 3.0 mmol) at room temperature, and the reaction mixture wasstirred at room temperature for 1 hour. The salt was filtered off, thesolvent was evaporated under reduced pressure, and the concentratedresidue was purified by silica gel column chromatography (n-hexane/ethylacetate) to give a crude product of Compound (IVb), which was used inthe next step without further purification. The resulting Compound (IVb)was dissolved in tetrahydrofuran (14 mL), lithium aluminum hydride (131mg, 3.4 mmol) was added thereto in small portions at room temperature,and the reaction mixture was stirred for 30 minutes. To the reactionsolution were added water (150 μL), 2 mol/L aq. NaOH (150 μL) and water(450 μL). The mixture was stirred at room temperature for 20 minutes,the resulting precipitate was filtered off through Celite, the filtratewas concentrated, and the concentrated residue was purified by silicagel column chromatography (n-hexane:ethyl acetate=1:1--->ethyl acetate)to give Compound (Vb) (608 mg, 72%).

Steps (iv) to (v)

To a solution of the Compound (Vb) (607 mg, 2.1 mmol) and triethylamine(282 μL, 4.2 mmol) in dichloromethane (6.2 mL) was added methanesulfonylchloride (239 μL, 3.1 mmol) at 0° C., and the reaction mixture wasstirred at the same condition for 30 minutes. To the mixture was added40% methylamine-methanol (6.2 mL) in small portions, and the reactionmixture was stirred overnight with slowly warming to room temperature.To the resultant was added sat. aq. NaHCO₃, the mixture was extractedwith 10% methanol-chloroform, the organic layer was dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to give acrude product of Compound (VIb), which was used in the next step withoutfurther purification. The resulting Compound (VIb) and triethylamine(282 μL, 4.2 mmol) were dissolved in dichloromethane (10 mL),di-tert-butyl dicarbonate (900 mg, 4.1 mmol) was added thereto at roomtemperature, and the reaction mixture was stirred at room temperaturefor 30 minutes. To the mixture was added sat. aq. NaHCO₃, and themixture was extracted with chloroform. The organic layer was dried overanhydrous Na₂SO₄, the solvent was evaporated under reduced pressure, andthe concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=95:5--->60:40) to give Compound(VIIb) (643 mg, 76%).

Step (vi)

The Compound (VIIb) (300 mg, 0.74 mmol) was hydrogenated in methanol (2mL) with 10% palladium carbon (30 mg) at room temperature over 1 hour atambient pressure. The catalyst was filtered off through Celite and thefiltrate was concentrated to give the title Compound (VIIIb) (243 mg,quantitative).

¹H-NMR (300 MHz, CDCl₃) δ: 1.45 (9H, s), 2.84 (3H, br s), 3.25 (2H, brs), 4.09 (2H, br s), 4.82 (2H, s), 7.27-7.37 (5H, m).

Reference Example 37 tert-Butyl{[5-oxo-1-(2-phenylethyl)-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

The title compound was prepared in the same manner as in ReferenceExample 36.

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 2.85 (3H, br s), 2.99 (2H, brt, J=7.6 Hz), 3.17 (2H, br s), 3.87-3.92 (2H, m), 4.12 (2H, br s),7.18-7.32 (5H, m).

Preparation of Hydrazine Compounds: Reference Example 38(Cyclohexylmethyl)hydrazine dihydrochloride

Step (i)

To a solution of cyclohexylaldehyde (38 g, 339 mmol) in methanol (677mL) was added N-Boc-hydrazine (44.8 g, 339 mmol) at room temperature,and the reaction mixture was stirred at room temperature for 3 hours.The solvent was evaporated under reduced pressure, to the concentratedresidue was added hexane (100 mL), and the mixture was suspended. Theresulting precipitate was collected by filtration to give Compound (Ic)(55.9 g) as a white solid. The filtrate was concentrated, to theconcentrated residue was added n-hexane (30 mL), and the resultingprecipitate was collected by filtration and washed with n-hexane (15 mL)to give Compound (Ic) (14.3 g, 70.2 g in total, 91%) as a white solid.

Steps (ii) to (iii)

To a solution of sodium cyanoborohydride (12.5 g, 189 mmol) in a mixtureof methanol (430 mL) and acetic acid (40 mL) was added the Compound (Ic)(42.8 g, 189 mmol) over 10 minutes with cooling in an ice bath to keepthe internal temperature below 15° C. The reaction mixture was stirredfor 30 minutes, and then for further 30 minutes with slowly warming toroom temperature. The mixture was adjusted to pH 8 with 2 mol/L aq. NaOH(50 mL) with cooling in the ice bath again, and extracted withchloroform (×2, 300 mL and 50 mL). The combined organic layers werewashed with sat. aq. NaHCO₃ (200 mL) and brine (200 mL), and dried overanhydrous Na₂SO₄. The solvent was evaporated under reduced pressure togive a crude product of Compound (IIc) (46.3 g) as an oil, which wasused in the next step without further purification. The resultingCompound (IIc) was dissolved in methanol (400 mL), and conc. HCl (100mL) was added dropwise to the solution at 55° C. over 30 minutes. Thereaction mixture was stirred at 55° C. to 60° C. for 1 hour and cooledto room temperature, and the solvent was evaporated under reducedpressure. To the concentrated residue was added methanol (200 mL), andthe solvent was evaporated under reduced pressure twice. To theconcentrated residue was added ethyl acetate (200 mL), the mixture wasstirred at room temperature, and the resulting precipitate was collectedby filtration to give the title Compound (IIIc) (39.4 g) as a whitepowder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (2H, br dd, J=22.6, 11.7 Hz),1.09-1.26 (3H, m), 1.55-1.78 (6H, m), 2.72 (2H, br d, J=4.4 Hz).

The following hydrazine compounds were prepared in the same manner as inReference Example 38 except that a corresponding ketone compound wasused.

Reference Example 39 (1-Cyclohexylethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.85-1.32 (8H, m), 1.53-1.80 (6H, m), 2.92(1H, dq, J=6.8, 5.4 Hz), 8.37 (5H, br s).

Reference Example 40 (1-Cyclohexylpropyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (3H, t, J=7.4 Hz), 0.96-1.28 (5H, m),1.50 (2H, m), 1.55-1.76 (6H, m), 2.64 (1H, dt, J=5.6, 5.6 Hz), 7.06 (5H,br s).

Reference Example 41 Pentan-3-ylhydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.85 (6H, t, J=7.1 Hz), 1.54 (4H, m), 2.81(1H, quin, J=5.9 Hz).

Reference Example 42 Ethyl cyclohexyl(hydrazinyl)acetate dihydrochloride

Steps (i) to (ii)

A solution of α-Ketoester (Id) (887 mg, 4.8 mmol) prepared according tothe method disclosed in Tetrahedron, 1996, 52 (42), 13513 and tert-butylcarbazate (636 mg, 4.8 mmol) in toluene (5 mL) was heated under refluxfor 1 day. The mixture was cooled to room temperature, and the solventwas evaporated under reduced pressure to give a crude product ofCompound (IId), which was used in the next step without furtherpurification. The resulting Compound (IId) was dissolved in methanol (24mL) and acetic acid (2.4 mL), to the solution was added sodiumcyanohydride (603 mg, 9.6 mmol) in a water bath to keep the temperatureat room temperature, and the reaction mixture was heated under refluxovernight. To the reaction solution was added water (10 mL) with coolingin an ice bath, sat. aq. NaHCO₃ was added thereto, and the mixture wasextracted with chloroform. The organic layer was dried over anhydrousNa₂SO₄, the solvent was evaporated under reduced pressure, and theconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1) to give Compound (IIId) (482 mg, 33%) as acolorless oil.

Step (iii)

To a solution of the Compound (IIId) (377 mg, 1.3 mmol) in ethanol (2.5mL) was added 4 mol/L HCl/1,4-dioxane (1.9 mL) at room temperature, andthe reaction solution was stirred at 50° C. for 35 minutes. To themixture was further added 4 mol/L HCl/1,4-dioxane (0.3 mL), and thereaction solution was stirred at 50° C. for 30 minutes. The reactionsolution was cooled to room temperature, and the solvent was evaporatedunder reduced pressure. The concentrated residue was purified by addingdiethyl ether and removing the supernatant by decantation to give thetitle Compound (IVd) (238 mg, 80%) as a white solid.

Reference Example 43 (Cyclopentylmethyl)hydrazine dihydrochloride

To a solution of cyclopentylmethyl alcohol (51.1 g, 0.51 mol) andtriethylamine (82.6 g, 0.82 mol) in tetrahydrofuran (510 mL) was addeddropwise methanesulfonyl chloride (67.2 g, 0.59 mmol) over 55 minuteswith keeping the temperature below 10° C., and the reaction mixture wasstirred for 1 hour. To the mixture was added water (380 mL) with keepingthe internal temperature below 10° C., and the mixture was extractedwith toluene (765 mL). The organic layer was dried over anhydrous MgSO₄,and the solvent was evaporated under reduced pressure to give a crudeproduct of Compound (Ie) (86.9 g). The crude product of Compound (Ie)(50 g, equivalent to 0.28 mol) and hydrazine monohydrate (84.3 g, 1.7mol) were dissolved in ethanol (281 mL), and the reaction mixture wasstirred at 45° C. to 55° C. for 7 hours and then cooled to roomtemperature. To the resultant was added water (94 mL), and the mixturewas extracted with chloroform (562 mL). The organic layer was washedwith water (94 mL) twice, and dried over anhydrous Na₂SO₄. To thesolution was added conc. HCl (85 g) at an internal temperature below 10°C., methanol (190 mL) was added thereto to dissolve the solid, and thesolvent was evaporated under reduced pressure. To the concentratedresidue was added 2-propanol (234 mL), and the solvent was evaporatedunder reduced pressure four times. To the concentrated residue was added2-propanol (85 mL). The mixture was heated to 40° C., n-hexane (170 mL)was added dropwise thereto at 40° C. over 30 minutes, and the mixturewas stirred at 40° C. for 1 hour. Then, the mixture was cooled to 10° C.over 1 hour and stirred at an internal temperature below 10° C. for 1hour. The resulting precipitate was collected by filtration, washed witha mixed solution of cooled n-hexane/2-propanol (2:1) (36 mL), and driedunder reduced pressure to give the title compound (33.6 g, 64%) as awhite powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.12-1.26 (2H, m), 1.42-1.65 (4H, m),1.67-1.81 (2H, m), 2.02-2.17 (1H, m), 2.84 (2H, d, J=7.3 Hz), 7.16 (5H,br s).

The compounds in Reference Examples 44 to 60 were prepared in the samemanner as in Reference Example 43 except that a corresponding alkylchloride, alkyl bromide, alkyl iodide or alkyl methanesulfonate wasused.

Reference Example 44 (Cyclopropylmethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.32 (2H, br dt, J=8.1, 3.1 Hz), 0.53 (2H,br ddd, J=9.4, 5.0, 3.1 Hz), 0.94-1.09 (1H, m), 2.81 (2H, d, J=7.2 Hz),8.21 (5H, br s).

Reference Example 45 (Cyclobutylmethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.67-1.92 (4H, m), 1.98-2.07 (2H, m),2.52-2.61 (1H, m), 2.94 (2H, d, J=7.3 Hz), 7.68 (5H, br s).

Reference Example 46 (Cycloheptylmethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.11-1.23 (2H, m), 1.33-1.82 (11H, m), 2.73(2H, d, J=6.8 Hz), 7.51 (5H, br s).

Reference Example 47 (2-Cyclohexylethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, CD₃OD) δ: 0.99 (2H, m), 1.15-1.40 (4H, m), 1.52 (2H,m), 1.63-1.79 (5H, m), 3.06 (2H, m).

Reference Example 48 (2-Cyclopentylethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.05 (2H, m), 1.38-1.63 (6H, m), 1.65-1.82(3H, m), 2.87 (2H, t, J=8.0 Hz), 5.73 (5H, br s).

Reference Example 49 [(4-Methylcyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.87 (3H, d, J=7.7 Hz), 0.85-1.85 (10H, m),2.83 (2H, d, J=7.0 Hz), 746 (3H, br s).

Reference Example 50 [(1-Methylcyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.91 (3H, s), 1.16-1.50 (10H, m), 2.72 (2H,s), 7.62 (3H, br s).

Reference Example 51 [(2-Methylcyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.95 (3H, d, J=7.0 Hz), 1.30-1.74 (8H, m),2.02 (1H, m), 2.22 (1H, m), 3.52 (2H, m), 4.75 (5H, br s).

Reference Example 52 [(4,4-Difluorocyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, CD₃OD) δ: 1.34 (2H, m), 1.66-1.93 (5H, m), 2.06 (2H, m)2.90 (2H, d, J=6.8 Hz).

Reference Example 53 [(1-Fluorocyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.14-1.86 (10H, m), 3.00 (2H, d, J=21.1Hz).

Reference Example 54 (3,3-Dimethylbutyl)hydrazine dihydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.87 (9H, s), 1.47 (2H, br dd, J=10.4, 7.0Hz), 2.86-2.93 (2H, m), 8.95 (5H, br s).

Reference Example 55 (2,2-Dimethylpropyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (9H, s), 2.65 (2H, s), 7.43 (5H, brs).

Reference Example 56 (2-Ethylbutyl)hydrazine dihydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.83 (6H, t, J=7.4 Hz), 1.24-1.40 (4H, m),1.52 (1H, dq, J=25.6, 6.5 Hz), 2.80 (2H, d, J=6.6 Hz), 8.54 (5H, br s).

Reference Example 57 (3-Methylbutyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 1.46 (2H, tt,J=6.5, 3.0 Hz), 1.61 (1H, dq, J=26.8, 6.6 Hz), 2.89-2.94 (2H, m), 6.47(5H, s).

Reference Example 58 (Bicyclo[2.2.1]hept-2-ylmethyl)hydrazinedihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.00-1.18 (4H, m), 1.21-1.53 (4H, m),1.64-1.75 (1H, m), 2.18 (2H, br s), 2.58-2.90 (2H, m), 6.98 (3H, br s).

Reference Example 59 (4,4,4-Trifluorobutyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.76 (2H, m), 2.34 (2H, m), 2.93 (2H, t,J=7.4 Hz), 8.80 (5H, br s).

Reference Example 60 (3-Methoxy-3-methylbutyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.10 (6H, s), 1.72-1.80 (2H, m), 2.91-2.99(2H, m), 3.09 (3H, s), 5.18 (5H, br s).

Reference Example 61: Hydrazine 3-bicyclo(7-Oxabicyclo[2.2.1]hept-2-ylmethyl)hydrazine dihydro-chloride

Steps (i) to (iii)

The compounds were prepared according to the methods disclosed inTeterahedron Letters, 23 (50), 5299. A mixed solution of furan (3.0 mL,41 mmol), ethyl acrylate (3.00 g, 30 mmol) and zinc iodide (2.87 g, 9.0mmol) was stirred at 40° C. for 1 day. The mixture was extracted withethyl acetate, and filtered through a mixture of silica gel and Celite.The filtrate was concentrated to give a crude product of Compound (If)(6.34 g), which was used in the next step without further purification.The resulting Compound (If) was hydrogenated in methanol (30 mL) with 5%palladium carbon (700 mg) overnight at ambient pressure. The catalystwas filtered off through Celite, and the filtrate was concentrated underreduced pressure to give a crude product of Compound (IIf) (3.70 g),which was used in the next step without further purification. Theresulting Compound (IIf) was dissolved in tetrahydrofuran (90 mL), tothe solution was added lithium aluminum hydride (1.20 g, 32 mmol) insmall portions at 0° C., and the reaction mixture was stirred at 0° C.for 30 minutes. To the reaction solution were subsequently added water,2 mol/L aq. NaOH and then water, the mixture was stirred at roomtemperature, and the resulting precipitate was filtered off throughCelite. The filtrate was concentrated, and the concentrated residue waspurified by silica gel column chromatography (n-hexane:ethyl acetate) togive Compound (IIIf) (2.40 g, 63%).

Step (iv)

To a solution of the Compound (IIIf) (2.40 g, 19 mmol) and triethylamine(5.2 mL, 38 mmol) in dichloromethane (30 mL) was added methanesulfonylchloride (2.2 mL, 28 mmol) at 0° C., and the reaction solution wasstirred at 0° C. for 30 minutes. To the solution was added sat. aq.NaHCO₃, the mixture was extracted with chloroform, the combined organiclayers were dried over anhydrous Na₂SO₄, and the solvent wasconcentrated under reduced pressure. The concentrated residue wasdissolved in ethanol (19 mL), to the solution was added hydrazinemonohydrate (5.63 g, 113 mmol), and the reaction mixture was stirred atroom temperature for 5 days and then at 60° C. for 8 hours. The mixturewas cooled to room temperature and the solvent was evaporated underreduced pressure. To the concentrated residue was added sat. aq. NaHCO₃,the mixture was extracted with chloroform, the combined organic layerswere dried over anhydrous Na₂SO₄, and the solvent was evaporated underreduced pressure. The concentrated residue was dissolved intetrahydrofuran (16 mL), to the solution was added 4 mol/LHCl/1,4-dioxane (16 mL) at room temperature, and the mixture was stirredat room temperature overnight. The resulting precipitate was collectedby filtration and dried under reduced pressure to give the titleCompound (IVf) (2.91 g, 87%) as a white powder.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.15-2.07 (7H, m), 2.59-2.82 (1H, m),2.92-3.72 (1H, m), 4.44-4.49 (2H, m), 5.74 (5H, s)

Reference Example 62: Hydrazine 4-bicyclo(2-Oxabicyclo[2.2.2]oct-3-ylmethyl)hydrazine dihydro-chloride

Steps (i) to (ii)

The compounds were prepared according to the methods disclosed inTeterahedron, 52(21), 7321. To a solution of copper (II) triflate (88mg, 0.24 mmol) and2,2′-iso-propylidenebis[(4S)-4-tert-butyl-2-oxazoline] (108 mg, 0.37mmol) in dichloromethane (5 mL) was subsequently added at roomtemperature a solution of cyclohexadiene (4.7 mL, 49 mmol) indichloromethane (10 mL) and then freshly prepared ethyl glyoxylatemonomer (5.0 g, 49 mmol), and the reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with diethyl ether andfiltered through silica gel, and the filtrate was concentrated to give acrude product of Compound (Ig) (2.65 g), which was used in the next stepwithout further purification. The resulting Compound (Ig) (1.58 g) washydrogenated with 10% palladium carbon (158 mg) in methanol (10 mL) atroom temperature over 2.5 hours at ambient pressure. The catalyst wasfiltered off through Celite, the filtrate was concentrated, and theconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=90:10--->75:25) to give Compound (IIg) (460 mg,9%).

Step (iii)

To a solution of the Compound (IIg) (199 mg, 1.1 mmol) intetrahydrofuran (10 mL) was added lithium borohydride (70 mg, 3.2 mmol)at room temperature, and the reaction mixture was stirred at roomtemperature for 1 hour. To the reaction solution was added dropwise aq.NH₄Cl at 0° C., and the mixture was extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous Na₂SO₄, the solventwas evaporated under reduced pressure, and the concentrated residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=70:30--->30:70) to give Compound (IIIg) (120 mg, 78%).

Step (iv)

To a solution of the Compound (IIIg) (440 mg, 3.0 mmol) andtriethylamine (878 μL, 6.3 mmol) in dichloro-methane (9 mL) was addedmethanesulfonyl chloride (366 μL, 4.7 mmol) at 0° C., and the reactionsolution was stirred at 0° C. for 30 minutes. To the solution was addedsat. aq. NaHCO₃, the mixture was extracted with chloroform, the combinedorganic layers were dried over anhydrous Na₂SO₄, and the solvent wasconcentrated under reduced pressure. The concentrated residue wasdissolved in ethanol (3 mL), to the solution was added hydrazinemonohydrate (946 mg, 19 mmol), and the reaction mixture was stirred atroom temperature overnight and then at 100° C. for 4 hours. The mixturewas cooled to room temperature and the solvent was evaporated underreduced pressure. To the concentrated residue was added sat. aq. NaHCO₃,the mixture was extracted with chloroform, the combined organic layerswere dried over anhydrous Na₂SO₄, and the solvent was evaporated underreduced pressure. The concentrated residue was dissolved intetrahydrofuran (5 mL), to the solution was added 4 mol/L HCl/dioxane(3.5 mL) at room temperature, and the mixture was stirred at roomtemperature for 30 minutes and then at 0° C. for 30 minutes. Theresulting precipitate was collected by filtration and dried underreduced pressure to give the title Compound (IVg) (220 mg, 31%) as awhite powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.45-1.92 (9H, m), 2.91 (1H, dd, J=12.0,4.7 Hz), 3.07 (1H, dd, J=11.9, 8.6 Hz), 3.53 (5H, br s), 3.68-3.74 (1H,m), 3.93-3.99 (1H, m).

Reference Example 63 (Tetrahydro-2H-pyran-2-ylmethyl)hydrazinedihydrochloride

Step (i)

The compound was prepared according to the method disclosed in Synlett,2004, 13, 2355. A solution of N-Boc-hydrazine (50 g, 378 mmol),anhydrous MgSO₄ (10 g) and acetic acid (25 drops) in acetone (375 mL)was heated under reflux for 2 hours. The mixture was cooled to roomtemperature, the resulting precipitate was filtered off, and thefiltrate was concentrated under reduced pressure to give Compound (Ih)(65.1 g, quantitative) as a white solid.

Steps (ii) to (iii)

A solution of the Compound (Ih) (10 g, 58 mmol),2-(tetrahydropyranyl)methylbromide (10 mL, 81 mmol), potassium hydroxide(4.89 g, 87 mmol) and tetrabutyl-ammonium sulfate (1.97 g, 5.8 mmol) intoluene (200 mL) was heated under reflux for 9 hours. To the reactionmixture was added water (200 mL), and the aqueous layer was extractedwith ethyl acetate (200 mL). The combined organic layers were dried overanhydrous MgSO₄ and the solvent was evaporated under reduced pressure.The concentrated residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give Compound (IIh) (9.30 g).The Compound (IIh) was dissolved in a mixed solvent of methanol (65 mL)and chloroform (30 mL), to the solution was added 4 mol/LHCl/1,4-dioxane (65 mL) at room temperature, and the reaction mixturewas stirred at 50° C. for 1 hour. The solvent was evaporated underreduced pressure, to the concentrated residue was added ethyl acetate(100 mL), and the mixture was stirred for 1 hour at room temperature.The resulting precipitate was collected by filtration, washed with ethylacetate (5 mL) twice, and dried under reduced pressure to give the titleCompound (IIIh) (6.79 g, 70%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.12-1.28 (1H, m), 1.37-1.59 (4H, m),1.70-1.85 (1H, m), 2.83-2.94 (2H, m), 3.30-3.42 (1H, m), 3.49-3.60 (1H,m), 3.84-3.94 (1H, m), 7.69 (5H, brs).

The following hydrazine compounds were prepared in the same manner as inReference Example 63 except that a corresponding alkyl chloride, alkylbromide, alkyl iodide, methanesulfonate and the like were used.

Reference Example 64 [(3-Methylcyclohexyl)methyl]hydrazinedihydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.90 (3H, d, J=6.6 Hz), 1.05-2.05 (10H, m),3.13 (2H, d, J=6.8 Hz), 5.86 (3H, br s).

Reference Example 65 (Cyclopentylmethyl)hydrazine phosphate

To a solution of cyclopentyl methanol (22.3 g, 0.22 mol) andtriethylamine (33.8 g, 0.33 mol) in tetra-hydrofuran was added dropwisemethanesulfonyl chloride (29.3 g, 0.26 mol) with keeping the temperaturebelow 15° C. over 50 minutes, and the reaction mixture was stirred atthe same condition for 1 hour. To the mixture was added dropwise water(134 g) with keeping the internal temperature below 15° C. over 10minutes. To the resultant was further added toluene (232 g), and themixture was extracted. The organic layer was washed with water (134 g),and the solvent was evaporated under reduced pressure to give a crudeproduct of Compound (Ie) (40.0 g), which was used in the next stepwithout further purification. The resulting Compound (Ie) and hydrazinemonohydrate (66.9 g, 1.34 mol) were dissolved in ethanol (178 g), andthe reaction mixture was stirred at 60° C. to 65° C. (internaltemperature) for 7 hours. The mixture was cooled to room temperature,and partitioned between chloroform (674 g) and water (71.5 g). Thechloroform layer was washed with water (71.5 mL, ×2) to give a solutionof a free base of Compound (IIff) in chloroform (808 g). To the solution(202 g, equivalent to 55 mmol) were added at room temperature 85%phosphoric acid (6.42 g, 60 mmol) and then 2-propanol (30 g), and thesolvent was evaporated under reduced pressure. To the concentratedresidue was added 2-propanol (36.7 g), and the solvent was evaporatedunder reduced pressure (×4). To the concentrated residue (24 g) wasadded 2-propanol to adjust the total weight to 45 g, and the mixture wasstirred at 40° C. for 1 hour. The mixture was cooled to 5° C. over 1.5hours, and then stirred at 5° C. for 1 hour. The precipitate wascollected by filtration, washed with a mixed solution of 2-propanol(1.98 g) and n-hexane (3.47 g), and dried under reduced pressure to giveCompound (IIff) (9.33 g, 80%) as a white crystalline solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.14-1.19 (2H, m), 1.40-1.55 (4H, m),1.70-1.75 (2H, m), 2.00-2.10 (1H, m), 2.74 (2H, d, J=8.0 Hz), 7.15 (6H,br).

Reference Example 66 (Cyclopentylmethyl)hydrazine sulfate

To the solution of the free base of Compound (IIff) in Reference Example65 in chloroform (202 g, equivalent to 55 mmol) were added at roomtemperature conc. H₂SO₄ (98% r 5.57 g, 60 mmol) and then 2-propanol (30g). The solvent was evaporated under reduced pressure. To theconcentrated residue was added 2-propanol (36.7 g), and the solvent wasevaporated under reduced pressure (×4). To the concentrated residue(24.9 g) was added 2-propanol to adjust the total weight to 45 g, andthe mixture was stirred at 40° C. for 1 hour. The mixture was cooled to5° C. over 1.5 hours and then stirred at 5° C. for 1 hour. Theprecipitate was collected by filtration, washed with a mixed solution of2-propanol (1.98 g) and n-hexane (3.47 g), and dried under reducedpressure to give the title compound (8.77 g, 75%) as a white crystallinesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.14-1.21 (2H, m), 1.46-1.58 (4H, m),1.68-1.75 (2H, m), 1.99-2.07 (1H, m), 2.82 (2H, d, J=8.0 Hz), 7.95 (5H,br).

Reference Example 67 (3-Methylbutyl)hydrazine phosphate

To a solution of isoamyl alcohol (100 g, 1.13 mol) and triethylamine(173 mL, 1.25 mol) in tetrahydrofuran (1.13 L) was added dropwisemethanesulfonyl chloride (136 g, 1.19 mol) with keeping the internaltemperature below 17° C. over 1 hour, and the reaction mixture wasstirred at the same condition for 1 hour. To the resultant was addeddropwise water (1.0 L) with keeping the internal temperature below 13°C., and the mixture was extracted with toluene (1.7 L) The organic layerwas dried over anhydrous MgSO₄ and the solvent was evaporated underreduced pressure to give a crude product of Compound (Igg) (198 g),which was used in the next step without further purification. Theresulting Compound (Igg) and hydrazine monohydrate (339 g, 6.77 mol)were dissolved in ethanol (1.13 L), and the reaction mixture was stirredat 50° C. (internal temperature) for 2 hours. The mixture was cooled toroom temperature, and partitioned between chloroform (2.26 L) and water(339 mL). The chloroform layer was washed with water (339 mL, ×2) To thesolution of chloroform was added phosphoric acid (85%, 130 g, 1.13 mol)at room temperature, and the solvent was evaporated under reducedpressure. To the obtained white-solid was added 2-propanol (300 mL), andthe solvent was evaporated under reduced pressure (×3). To theconcentrated residue was added 2-propanol (1.13 L). The mixture wasstirred for 1.5 hours at 45° C. (internal temperature) and then stirredovernight with slowly cooling to room temperature. The resultingprecipitate was collected by filtration, washed with cold 2-propanol(100 mL, ×2), and dried under reduced pressure to give the titleCompound (IIgg) (181 g, 80%) as a white powder.

¹H-NMR (300 MHz, DMSO) δ: 0.85 (d, J=6.6 Hz, 6H), 1.39 (dd, J=15.2, 7.2Hz, 2H), 1.59 (sept, J=6.6 Hz, 1H), 2.68-2.84 (m, 2H), 7.13 (br s, 6H).

Reference Example 68 (3-Methylbutyl)hydrazine sulfate

To the compound of Reference Example 57 (3.50 g, 20 mmol) was added 10%aq. K₂CO₃, and the mixture was extracted with chloroform (30 mL×2+10mL). The chloroform layer was washed with brine and dried over anhydrousNa₂SO₄, and the solvent was evaporated under reduced pressure to give afree form of hydrazine (470 mg) as a yellow oil. Then 235 mg of theproduct (equivalent to 4.60 mmol) was dissolved in 2-propanol (5 g). Tothe solution were added at room temperature conc. H₂SO₄ (230 mg, 2.3mmol) and then n-hexane (5 mL), and the resulting precipitate wascollected by filtration and dried under reduced pressure to give thetitle compound (81 mg) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.87 (6H, d, J=6.6 Hz), 1.36-1.42 (2H, m),1.55-1.63 (1H, m), 2.88 (2H, t, J=8.0 Hz), 7.85 (5H, br).

Reference Example 69 [(1-Methoxycyclopentyl)methyl]hydrazinedihydrochloride

Step (i)

To a solution of Compound (Ihh) prepared according to the methoddisclosed in Organometallics, 6(10), 1987, 2079 (637 mg, 3.8 mmol) intetrahydrofuran (8.7 mL) was added borane tetrahydrofuran complex (1.1mol/L, 8.7 mL, 9.6 mmol) at room temperature, the reaction mixture wasstirred at room temperature overnight, and methanol (5 mL) was addedthereto. After the gas evolution ceased, the solvent was evaporatedunder reduced pressure, the concentrated residue was dissolved in amixed solution of chloroform and methanol (9:1), the mixture wasfiltered through silica gel, and the filtrate was concentrated. Theconcentrated residue was purified by silica gel column chromatography(chloroform:methanol=99:1--->90:10) to give Compound (IIhh) (420 mg,84%) as a colorless oil.

Steps (ii) to (iii)

Compound (IVhh) was prepared in the same manner as in Reference Example43.

¹H-NMR (300 MHz, CD₃OD) δ: 1.51-1.80 (6H, m), 1.93 (2H, m), 3.16 (2H,m), 3.23 (3H, s). 5H unditected (NH, NH₂, 2HCl)

Reference Example 70 [(1-Methoxycyclohexyl)methyl]hydrazinedihydrochloride

The title compound was prepared in the same manner as in ReferenceExample 69.

¹H-NMR (300 MHz, CD₃OD) δ: 1.36-1.61 (8H, m), 1.79 (2H, m), 3.07 (2H,s), 3.22 (3H, s). 5H unditected (NH, NH₂, 2HCl)

The compounds in Reference Examples 71 and 72 were prepared in the samemanner as in Reference Example 43 except that a corresponding alkylchloride, alkyl bromide, alkyl iodide or alkyl methanesulfonate wasused.

Reference Example 71 (3-Methoxybutyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO) δ: 1.05 (d, J=6.1 Hz, 3H), 1.52-1.94 (m, 2H),2.80-3.05 (m, 2H), 3.19 (s, 3H), 3.28-3.45 (m, 1H), 6.59 (br s, 5H).

Reference Example 72 (2-Cyclopropylethyl)hydrazine dihydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.05 (2H, m), 0.41 (2H, m), 0.71 (1H, m),1.43 (2H, q, J=7.3 Hz), 2.94 (2H, t, J=7.6 Hz). 5H unditected (NH, NH₂,2HCl)

Reference Example 73: 3-Et-amylhydrazine

(3-Ethylpentyl)hydrazine dihydrochloride

Step (i)

To a suspension of magnesium (729 mg, 33 mmol) in tetrahydrofuran (3 mL)was added Compound (Ikk) (1.5 g) To the resultant was further addeddropwise a solution of Compound (Ikk) (3.45 g) in anhydroustetrahydrofuran (40 mL), and the mixture was stirred for 40 minutes. Tothe reaction mixture was added dry ice (5 g), and the reaction mixturewas stirred for 3 hours with slowly warming to room temperature. To theresultant was added 1 N HCl, the mixture was extracted with ethylacetate, the organic layer was washed with brine and dried overanhydrous MgSO₄, and the solvent was evaporated under reduced pressureto give a crude product of Compound (IIkk) (3.80 g) as a colorless oil.

Steps (ii) to (iii)

The crude product of Compound (IIkk) (2.6 g, equivalent to 20 mmol) wasdissolved in tetrahydrofuran (40 mL), to the solution was added boranetetrahydrofuran complex (in 0.9 N tetrahydrofuran, equivalent to 60mmol) with ice-cooling, and the reaction mixture was stirred at the samecondition for 1 hour. To the mixture was added 1 N HCl, thetetrahydrofuran was evaporated under reduced pressure, and theconcentrated residue was extracted with ethyl acetate. The organic layerwas subsequently washed with sat. aq. NaHCO₃ and brine, and dried overanhydrous MgSO₄. The solvent was evaporated under reduced pressure togive a crude product of Compound (IIIkk) (2.96 g), which was used in thenext step without further purification. The resulting Compound (IIIkk)and triethylamine (3.5 mL, 25 mmol) were dissolved in tetrahydrofuran(40 mL), to the solution was added methanesulfonyl chloride (1.7 mL, 22mmol) with ice-cooling, and the reaction mixture was stirred for 30minutes. To the resultant was added water, the mixture was extractedwith ethyl acetate, the organic layer was dried over anhydrous MgSO₄,and the solvent was evaporated under reduced pressure. The concentratedresidue (4.35 g) and hydrazine monohydrate (6.0 g, 120 mmol) weredissolved in ethanol (20 mL), and the mixture was stirred at 50° C. for3 hours. The reaction mixture was cooled to room temperature, water wasadded thereto, and the mixture was extracted with chloroform. Theorganic layer was washed with water and dried over anhydrous Na₂SO₄. Tothe organic layer was added 4 N HCl/1,4-dioxane solution, and thesolvent was evaporated under reduced pressure. To the concentratedresidue were added 2-propanol (10 mL) and n-hexane (100 mL), and themixture was insonated. The resulting precipitate was collected byfiltration to give Compound (IVkk) (612 mg, 10%) as a white powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.80 (6H, t, J=7.5 Hz), 1.18-1.35 (5H, m),1.45-1.55 (2H, m), 2.86 (2H, d, J=7.5 Hz), 7.00 (5H, br).

The compounds in Reference Examples 74 to 78 were prepared in the samemanner as in Reference Example 1 except that the compounds in ReferenceExamples 69 to 73 were used.

Reference Example 74 tert-Butyl{[1-(2-cyclopropylethyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 0.04 (2H, m), 0.44 (2H, m), 0.67 (1H, m),1.47 (9H, s), 1.57 (2H, m), 2.87 (3H, s), 3.22 (2H, s), 3.74 (2H, t,J=7.2 Hz), 4.11 (2H, s).

Reference Example 75 tert-Butyl({1-[(l-methoxycyclopentyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (9H, s), 1.55-1.86 (8H, m), 2.87 (3H,s), 3.22 (2H, s), 3.27 (3H, s), 3.79 (2H, s), 4.11 (2H, br s).

Reference Example 76 tert-Butyl({1-[(1-methoxycyclohexyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.13-1.80 (10H, m), 1.46 (9H, s), 2.86 (3H,s), 3.21 (2H, s), 3.28 (3H, s), 3.64 (2H, s), 4.10 (2H, br s).

Reference Example 77 tert-Butyl{[1-(3-methoxybutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.17 (d, J=6.2 Hz, 3H), 1.47 (s, 9H),1.71-1.92 (m, 2H), 2.87 (s, 3H), 3.22 (s, 2H), 3.28-3.40 (m, 4H), 3.75(t, J=7.0 Hz, 2H), 4.12 (br s, 2H).

Reference Example 78 tert-Butyl{[1-(3-ethylpentyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}methylcarbamate

¹H-NMR (400 MHz, CDCl₃) δ: 0.83 (6H, t, J=8.0 Hz), 1.14-1.33 (5H, m),1.44 (9H, s), 1.56-1.62 (2H, m), 2.83 (3H, s), 3.19 (2H, s), 3.62 (2H,t, J=8.0 Hz, 8.0 Hz), 4.07-4.10 (2H, m).

Reference Example 79 tert-Butyl({1-[2-(1-hydroxycyclopentyl)ethyl]-5-oxo-4,5-dihydro-1H-pyrazol-3-yl}methyl)methylcarbamate

Step (i)

To a suspension of lithium aluminum hydride (1.83 g, 48 mmol) inanhydrous tetrahydrofuran (mL) was added dropwise a solution of Compound(Imm) prepared according to the method disclosed in Journal of OrganicChemistry, 69(3), 2004, 997 (4.16 g, 24 mmol) in anhydroustetrahydrofuran (mL) with heating under reflux, and then the reactionmixture was heated under reflux for 1 hour. To the mixture was addedsat. aq. Na₂SO₄ (7.3 mL) with cooling in an ice bath, and the mixturewas stirred for 2 hours with slowly warming to room temperature. To themixture was further added anhydrous Na₂SO₄, the solid was filtered off,and the filtrate was concentrated. The concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:4--->ethylacetate--->chloroform:methanol=10:1) to give Compound (IImm) (1.04 g,66%) as a colorless oil.

Steps (ii) to (iii)

To a solution of the Compound (IImm) (0.97 g, 7.5 mmol) andtriethylamine (1.56 g, 11 mmol) in dichloro-methane (15 mL) was addedmethanesulfonyl chloride (692 μL, 8.9 mmol) over 5 minutes withice-cooling, and the reaction mixture was stirred at ice temperature for20 minutes. To the mixture was added water, the mixture was extractedwith chloroform, the organic layer was washed with brine and dried overanhydrous Na₂SO₄, and the solvent was evaporated under reduced pressureto give a concentrated residue (1.59 g), which was used in the next stepwithout further purification. The concentrated residue (1.59 g) andhydrazine monohydrate (2.2 mL, 45 mmol) were dissolved in ethanol (7.5mL), and the mixture was stirred at 50° C. for 3 hours. The mixture wascooled to room temperature, water (1 mL) was added thereto, the mixturewas extracted with chloroform, and the organic layer was washed withwater and dried over anhydrous Na₂SO₄. To the organic layer was added 4N HCl-1,4-dioxane (7.5 mL), and the solvent was evaporated under reducedpressure to give a crude product of Compound (IIImm) (2.05 g), which wasused in the next step without further purification. The resultingCompound (IIImm) and triethylamine (1.3 mL, 9.0 mmol) were dissolved inethanol (7 ml), and the mixture was stirred at 50° C. for 10 minutes. Tothe mixture was added the Compound (IIa) (1.35 g, 5.2 mmol) in ReferenceExample 1, and the reaction mixture was stirred at 70° C. for 30minutes. The mixture was cooled to room temperature, 5% aq. KHSO₄ (50mL) was added thereto, the mixture was extracted with ethyl acetate (100mL), the organic layer was dried over anhydrous Na₂SO₄, and the solventwas evaporated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography to give the title Compound(IVmm) (217 mg, 37%) as a light brown solid.

¹H-NMR (CDCl₃) δ: 1.43-1.88 (8H, m), 1.47 (9H, s), 1.95 (2H, t, J=6.9Hz), 2.87 (3H, s), 3.23 (2H, s), 3.87 (2H, t, J=6.9 Hz), 4.12 (2H, brs). 1H unditected (OH)

Reference Example 80 tert-Butylmethyl[(5-oxo-1-{[1-(trifluoromethyl)cyclo-propyl]methyl}-4,5-dihydro-1H-pyrazol-3-yl)methyl]carbamate

Steps (i) to (iii)

To a suspension of lithium aluminum hydride (903 mg, 23.8 mmol) intetrahydrofuran (40 mL) was added dropwise Compound (Inn) (2.00 g, 11.9mmol) with ice-cooling, and the reaction mixture was stirred withice-cooling for 1 hour. To the reaction mixture were added water (0.9mL) and 15% aq. NaOH (0.9 mL), and then water (4.5 mL) was further addedthereto. The mixture was stirred with slowly warming to room temperatureand the resulting precipitate was filtered off. The filtrate was driedover anhydrous Na₂SO₄, and the solvent was evaporated under reducedpressure to give a crude product of Compound (IInn) (1.31 g, equivalentto 9.4 mmol), which was used in the next step without furtherpurification.

The resulting Compound (IInn) and triethylamine (2.0 mL, 14 mmol) weredissolved in tetrahydrofuran (19 mL), to the solution was addedmethanesulfonyl chloride (871 μL, 11 mmol) at ice temperature, and thereaction mixture was stirred at the same condition for 1.5 hours. Themixture was partitioned between ethyl acetate and water, and the organiclayer was washed with brine and dried over anhydrous Na₂SO₄. The solventwas evaporated under reduced pressure to give a crude product ofCompound (IIInn) (1.77 g), which was used in the next step withoutfurther purification.

The resulting Compound (IIInn) and hydrazine mono-hydrate (2.2 mL, 45mmol) were dissolved in ethanol (7 mL), and the reaction mixture wasstirred at ° C. for 3 hours. The mixture was cooled to room temperature,and partitioned between chloroform (40 mL) and water (2 mL). Thechloroform layer was washed with water (2 mL) and dried over anhydrousNa₂SO₄. To the resultant was added 10% HCl-methanol (20 mL), and thesolvent was evaporated under reduced pressure. To the concentratedresidue was added diethyl ether (3 mL), and the resulting precipitatewas collected by filtration and dried under reduced pressure to giveCompound (IVnn) (1.00 g, 44%).

Step (iv)

Compound (Vnn) was prepared in the same manner as in Reference Example1.

¹H-NMR (300 MHz, CDCl₃) δ: 0.87-0.95 (m, 2H), 1.00-1.08 (m, 2H), 1.47(s, 9H), 2.86 (s, 3H), 3.22 (s, 2H), 3.87 (s, 2H), 4.11 (br s, 2H).

The compounds of Reference Examples 81 and 82 were prepared in the samemanner as in Reference Example 80.

Reference Example 81 tert-Butylmethyl[(5-oxo-1-{[1-(trifluoromethyl)cyclo-butyl]methyl}-4,5-dihydro-1H-pyrazol-3-yl)methyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (s, 9H), 1.81-2.04 (m, 2H), 2.14-2.39(m, 4H), 2.86 (s, 3H), 3.25 (s, 2H), 3.93 (s, 2H), 4.12 (br s, 2H).

Reference Example 82 tert-Butylmethyl[(5-oxo-1-{[1-(trifluoromethyl)cyclo-pentyl]methyl}-4,5-dihydro-1H-pyrazol-3-yl)methyl]carbamate

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (s, 9H), 1.54-1.76 (m, 4H), 1.79-1.99(m, 4H), 2.86 (s, 3H), 3.22 (s, 2H), 3.82 (s, 2H), 4.12 (br s, 2H).

The compounds of Reference Examples 83 and 84 were prepared in the samemanner as in Reference Example 31.

Reference Example 83 tert-Butylmethyl{1-[1-(3-methylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]-ethyl}carbamate

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (6H, d, J=8.0 Hz), 1.37 (3H, d, J=8.0Hz), 1.44 (9H, s), 1.51-1.60 (3H, m), 2.65 (3H, s), 3.13 (2H, br s),3.60-3.66 (2H, m), 4.78 and 5.06 (1H, br s).

Reference Example 84 tert-Butylmethyl{1-[1-(4-methylpentyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]ethyl}carbamate

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (6H, t, J=6.6 Hz), 1.12-1.18 (2H, m),1.37 (3H, d, J=8.0 Hz), 1.44 (9H, s), 1.50-1.57 (1H, m), 1.60-1.68 (2H,m), 2.65 (3H, s), 3.14 (2H, br s), 3.56-3.61 (2H, m), 4.78 and 5.07 (1H,br).

Reference Example 85 Ethyl1-(cyclopentylmethyl)-5-hydroxy-1H-pyrazole-3-carboxylate

To a solution of the Compound (IIff) (77.6 g, 370 mmol) in ReferenceExample 65 in ethanol (504 g) was added dropwise triethylamine (92.5 g,910 mmol) at room temperature over 10 minutes, to the mixture was addedCompound (Ib) disclosed in Example 1 below (92.2 g, 440 mmol), and thereaction mixture was stirred at 30° C. for 5.5 hours. To the reactionmixture were added water (481 g) and conc. HCl (36%, 100 g) with keepingthe internal temperature below 30° C., and the ethanol was evaporatedunder reduced pressure. To the concentrated residue was added t-butylmethyl ether (660 g), and the organic layer was washed with water (489g) and then concentrated under reduced pressure. To the concentratedresidue (123 g) was added acetonitrile (310 g), and the mixture washeated at 70° C. After the solid was dissolved, the mixture was cooledto 60° C. The resulting precipitate was stirred at 60° C. for 1 hour,cooled to 5° C. (internal temperature) over 2 hours, and then stirred at5° C. for 1 hour. The resulting precipitate was collected by filtrationand washed with cold acetonitrile (23 g×3) to give the title compound(52.2 g, 60%) as a light brown powder.

¹H-NMR (300 MHz, DMSO) δ: 1.16-1.37 (m, 5H), 1.39-1.68 (m, 6H),2.22-2.43 (m, 1H), 3.82 (d, J=7.5 Hz, 2H), 4.19 (q, J=7.1 Hz, 2H), 5.74(s, 1H), 11.34 (br s, 1H).

Reference Example 86 tert-Butylmethyl{[l-(3-methylbutyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]methyl}carbamate

A solution of the title compound in Reference Example 67 (6.00 g, 30mmol) and triethylamine (10.5 mL, 75 mmol) in ethanol (60 mL) wasstirred at room temperature for 10 minutes, to the mixture was added theCompound (IIa) in Reference Example 1 (8.19 g, 30 mmol) at 60° C., andthe reaction mixture was stirred at 70° C. for 1 hour. The mixture wascooled to room temperature, 5% KHSO₄ (140 mL) was added thereto toadjust the pH to around pH 4, and the ethanol was evaporated underreduced pressure to give a concentrated residue (160 g). To the residuewas added ethyl acetate (120 mL), the aqueous layer was re-extractedwith ethyl acetate (20 mL), the combined organic layers were dried overanhydrous MgSO₄, and the solvent was evaporated under reduced pressure.To the concentrated residue was added ethyl acetate (30 mL), and themixture was heated to 70° C. After the solution was homogeneous,n-hexane (60 mL) was added dropwise to the solution at 70° C. Thesolution was slowly cooled to room temperature, and to the solution wereadded seed crystals (5 mg) of the title compound. The mixture wasstirred at room temperature for 1 hour, and then at ice temperature for1 hour. The resulting precipitate was collected by filtration, washedwith a mixed solution of cooled ethyl acetate/n-hexane (1:2, 12 mL), anddried under reduced pressure to give the title compound (6.33 g, 71%) asa white solid.

Reference Example 87 Ethyl5-hydroxy-1-(3-methylbutyl)-1H-pyrazole-3-carboxylate

A solution of the title compound in Reference Example 67 (50 g, 250mmol) and triethylamine (87 mL, 620 mmol) in ethanol (500 mL) wasstirred at room temperature, and then the solution was homogeneous. Tothe solution was added Compound (Ib) disclosed in Example 1 below (63 g,300 mmol), and the reaction mixture was stirred at room temperature for2 hours. At ice temperature, the reaction mixture was added dropwise toa mixed solution of 1 N HCl (600 mL) and water (500 mL) with keeping theinternal temperature below 20° C. The mixture was stirred for 1 hourwith keeping the internal temperature at 5° C., and the resultingprecipitate was collected by filtration and washed with cold water (100mL). The resulting solid was dried under reduced pressure at 50° C. togive a crude crystal of the title compound (44.8 g), and acetonitrile(200 mL) was added thereto. The mixture was stirred for 1 hour at 75°C., stirred for 3 hours with cooling to room temperature, and thenice-cooled for 1 hour. The resulting precipitate was collected on afilter and washed with cold acetonitrile (20 mL) to give the titlecompound (38.3 g, 68%) as a light brown powder.

¹H-NMR (300 MHz, DMSO) δ: 0.88 (d, J=6.2 Hz, 6H), 1.24 (t, J=7.1 Hz,3H), 1.37-1.53 (m, 1H), 1.57 (dd, J=14.3, 7.2 Hz, 2H), 3.91 (t, J=7.2Hz, 2H), 4.19 (q, J=7.1 Hz, 2H), 5.74 (s, 1H), 11.37 (br s, 1H).

Example 11-[1-Benzyl-5-(benzyloxy)-1H-pyrazol-3-yl]-N-methylmethan-aminehydrochloride

Steps (i) to (iii)

To a solution of Compound (IIIb′) (710 mg, 2.9 mmol) prepared in thesame manner as in Step (i) of Reference Example 31 except thatbenzylhydrazine and Compound (Ib) were used and K₂CO₃ (418 mg, 3.0 mmol)in DMF (8.6 mL) was added benzyl bromide (360 μL, 3.0 mmol) at roomtemperature, and the reaction mixture was stirred at room temperatureovernight. The salt was filtered off, and the solvent was evaporatedunder reduced pressure to give a crude product of Compound (IVb), whichwas used in the next step without further purification. The resultingCompound (IVb) was dissolved in tetrahydrofuran (14 mL), to the solutionwas added lithium aluminum hydride (131 mg, 3.5 mmol) in small portionsat 0° C., and the reaction mixture was stirred for 30 minutes. To thereaction solution were added water (150 μL), 2 mol/L aq. NaOH (150 μL)and water (450 μL), the mixture was stirred at room temperature, and theresulting precipitate was filtered off through Celite. The filtrate wasconcentrated, and the concentrated residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=50:50--->ethyl acetate) togive Compound (Vb) (608 mg, 72%).

Step (iv)

To a solution of the Compound (Vb) (607 mg, 2.1 mmol) and triethylamine(282 μL, 2.0 mmol) in dichloromethane (6.2 mL) was added methanesulfonylchloride (239 μL, 3.1 mmol) at 0° C., and the reaction mixture wasstirred at the same condition for 30 minutes. To the resultant was added40% methylamine-methanol (6.2 mL) in small portions, and the reactionmixture was stirred overnight with slowly warming to room temperature.To the resultant was added sat. aq. NaHCO₃, the mixture was extractedwith chloroform, the organic layer was dried over anhydrous Na₂SO₄, andthe solvent was evaporated under reduced pressure to give a crudeproduct, which was used in the next step without further purification.To a solution of the crude product and triethylamine (282 μL, 2.0 mmol)in dichloromethane (10 mL) was added di-tert-butyl dicarbonate (900 mg,4.1 mmol) at room temperature, and the reaction mixture was stirred atroom temperature for 30 minutes. To the resultant was added sat. aq.NaHCO₃, the mixture was extracted with chloroform, the organic layer wasdried over anhydrous Na₂SO₄, and the solvent was evaporated underreduced pressure to give a concentrated residue. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=95:5--->60:40) to give Compound (VIIb) (643 mg, 76%).

Step (v)

To a solution of the Compound (VIIb) (120 mg, 0.29 mmol) in chloroform(0.3 mL) was added 4 mol/L HCl/1,4-dioxane (0.9 mL) at room temperature,and the reaction solution was stirred at room temperature for 1 hour.The solvent was evaporated under reduced pressure, the concentratedresidue was purified by adding diethyl ether and removing thesupernatant by decantation, and the resultant solid was evaporated underreduced pressure to give the title Compound (VIb′) (102 mg,quantitative) as a white powder.

¹H-NMR (300 MHz, CD₃OD) δ: 2.67 (3H, s), 4.05 (2H, br s), 5.17 (2H, brs), 5.18 (2H, br s), 5.85 (1H, s), 7.17 (2H, dd, J=7.3, 2.2 Hz),7.25-7.31 (3H, m), 7.33 (5H, br s). Obs MS [M+1]: 308.4

Examples 2 to 7

The compounds of Examples 2 to 7 as shown in Table 1 were prepared inthe same manner as in Example 1.

TABLE 1

Ex. R Salt 2□

Free base 3□

Free base 4□

Free base 5□

Free base 6□

Free base 7□

Free base (* shows the bonding position)

Example 21-[5-(Benzyloxy)-1-(2-phenylethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 2.47 (3H, s), 3.06 (2H, t, J=7.4 Hz), 3.67(2H, s), 4.15 (2H, t, J=7.4 Hz), 4.88 (2H, s), 5.49 (1H, s), 7.08 (2H,dt, J=7.1, 2.3 Hz), 7.17-7.28 (4H, m), 7.32-7.41 (4H, m).

Obs MS [M+1]: 322.4

Example 31-[5-(Benzyloxy)-1-(3-phenylpropyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 2.04-2.14 (2H, m), 2.46 (3H, s), 2.56-2.62(2H, m), 3.65 (2H, s), 3.96 (2H, t, J=7.1 Hz), 5.05 (2H, s), 5.55 (1H,s), 7.12-7.44 (10H, m).

Example 41-[5-(Benzyloxy)-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 1.20-1.29 (2H, m), 1.47-1.69 (6H, m),2.35-2.44 (1H, m), 2.45 (3H, br s), 3.64 (2H, s), 3.84 (2H, d, J=7.6Hz), 5.05 (2H, s), 5.53 (1H, s), 0.7.34-7.42 (5H, m).

Obs MS [M+1]: 300.3

Example 51-[5-(Benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.94 (2H, dd, J=23.6, 11.5 Hz), 1.13-1.20(3H, m), 1.53-1.72 (5H, m), 1.79-1.91 (1H, m), 2.46 (3H, s), 3.64 (2H,s), 3.75 (2H, d, J=7.3 Hz), 5.05 (2H, s), 5.52 (1H, s), 7.35-7.40 (5H,m).

Obs MS [M+1]: 314.3

Example 61-[5-(Benzyloxy)-1-(cycloheptylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 1.12-1.21 (2H, m), 1.41-1.57 (10H, m),2.06-2.10 (1H, m), 2.45 (3H, s), 3.64 (2H, s), 3.73 (2H, d, J=7.5 Hz),5.05 (2H, s), 5.52 (1H, s), 7.35-7.41 (5H, m).

Obs MS [M+1]: 328.6

Example 71-[5-(Benzyloxy)-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 1.21-1.34 (1H, m), 1.37-1.61 (4H, m), 1.81(1H, br d, J=10.1 Hz), 2.45 (3H, br s), 3.39 (1H, td, J=11.4, 2.6 Hz),3.64 (2H, s), 3.66-3.78 (1H, m), 3.85 (1H, dd, J=13.9, 5.9 Hz),3.93-4.00 (1H, m), 4.06 (1H, dd, J=13.8, 6.9 Hz), 5.07 (2H, s), 5.52(1H, s), 7.33-7.41 (5H, m).

Example 81-{1-Benzyl-5-[(2-chlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (VIIIb) prepared in Reference Example 36(20 mg, 0.063 mmol) and cesium carbonate (31 mg, 0.95 mmol) in DMF (0.2mL) was added 2-chlorobenzyl chloride (12 μL, 0.095 mmol) at 0° C., andthe reaction mixture was stirred overnight with slowly warming to roomtemperature. The salt was filtered off, the filtrate was concentrated,and the concentrated residue was purified by PTLC (toluene:ethylacetate=30:70) to give the title Compound (IIk) (24 mg, 85%).

Step (ii)

To a solution of the Compound (IIk) (24 mg, 0.054 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (0.5 mL) at room temperature,and the reaction solution was stirred at room temperature for 30minutes. The solvent was evaporated under reduced pressure, theconcentrated residue was purified by adding diethyl ether and removingthe supernatant by decantation, and the resultant solid was evaporatedunder reduced pressure to give the title Compound (IIIk) (20 mg, 97%) asa white powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.54 (3H, br s), 4.00 (2H, s), 5.15 (2H,s), 5.26 (2H, s), 6.00 (1H, s), 7.15 (2H, td, 3.9, 2.0 Hz), 7.24-7.45(5H, m), 7.53 (2H, dt, J=7.5, 1.7 Hz), 8.91 (2H, br s).

Obs MS [M+1]: 342.3

Examples 9 to 13

The compounds of Examples 9 to 13 as shown in Table 2 were prepared inthe same manner as in Example 8 except that a corresponding benzylbromide or benzyl chloride was used.

TABLE 2

Ex. X Obs MS [M + 1]  9□ 3-Cl 342.3 10□ 4-Cl 342.3 11□ 2-Me 322.4 12□3-Me 322.4 13□ 4-Me 322.4

Examples 14 to 19

The compounds of Examples 14 to 19 as shown in Table 3 were prepared inthe same manner as in Example 8 except that the compound obtained inReference Example 37 and a corresponding benzyl bromide or benzylchloride were used.

TABLE 3

Ex. X Obs MS [M + 1] 14□ 2-Cl 356.3 15□ 3-Cl 356.3 16□ 4-Cl 356.3 17□2-Me 336.4 18□ 3-Me 336.4 19□ 4-Me 336.4

Examples 20 to 40

According to the general process below, the compounds of Examples 20 to40 as shown in Table 4 were prepared.

General Process of Compound (IIIm)

Compound (Im) prepared in Reference Example 4 and a corresponding benzylbromide or benzyl chloride were used to prepare Compound (IIIm). Step(i) was carried out by any of the following Method A, B or C.

Step (i): Alkylation Reaction Method A:

To a solution of Compound (Im) prepared in Reference Example 4 (20 mg,0.063 mmol) and cesium carbonate (1.5 equivalent, 31 mg, 0.095 mmol) indimethylformamide (0.2 mL) was added a corresponding benzyl chloride(1.5 equivalent, 0.095 mmol) at 0° C., and the reaction mixture wasstirred for 2 days with slowly warming to room temperature. The salt wasfiltered off, and the solvent was evaporated under reduced pressure togive a crude product of Compound (IIm). If necessary, the crude productof Compound (IIm) was purified by silica gel column chromatography(n-hexane:ethyl acetate=50:50) or PTLC (toluene:ethyl acetate=70:30).

Method B:

To a solution of Compound (Im) (100 mg, 0.31 mmol) and silver oxide (79mg, 0.34 mmol) in acetonitrile (1 mL) was added a solution of acorresponding benzyl bromide (1.5 equivalent, 0.46 mmol) in acetonitrile(2 mL) at room temperature, and the reaction mixture was stirred at roomtemperature for 2 hours. To the solution was added ethyl acetate, thesalt was filtered off, and the filtrate was concentrated to give a crudeproduct of Compound (IIm). If necessary, the crude product of Compound(IIm) was purified by silica gel column chromatography (n-hexane ethylacetate=50:50) or PTLC (toluene: ethyl acetate=70:30).

Method C:

To a solution of Compound (Im) (100 mg, 0.31 mmol) and cesium carbonate(1.5 equivalent, 151 mg, 0.46 mmol) in acetonitrile (1 mL) was added asolution of a corresponding benzyl bromide (1.5 equivalent, 0.46 mmol)in acetonitrile (2 mL) at room temperature, and the reaction mixture wasstirred at room temperature for 18 hours. To the solution was addedethyl acetate, the salt was filtered off, and the filtrate wasconcentrated to give a crude product of Compound (IIm). If necessary,the crude product of Compound (IIm) was purified by silica gel columnchromatography (n-hexane:ethyl acetate=50:50) or PTLC (toluene: ethylacetate=70:30).

Step (ii): Deprotection of N-Boc Group

The Compound (IIm) was dissolved in chloroform (1 mL), 4 mol/LHCl/1,4-dioxane (2 mL) was added to the solution at room temperature,the reaction mixture was stirred for 2 hours, and the solvent wasevaporated under reduced pressure. The residue was purified by addingdiethyl ether and removing the supernatant by decantation, and theresulting solid was dried under reduced pressure to give a hydrochlorideof Compound (IIIm). If necessary, the concentrated residue was purifiedby reversed-phase liquid chromatography (0.05% trifluoroaceticacid--->aceto-nitrile/0.05% trifluoroacetic acid/water) to give afraction of Compound (IIIm), and the compound in the fraction wasconverted to a free base of Compound (IIIm) by a typical method.

The reversed-phase liquid chromatography can be carried out under, forexample, the following conditions:

Apparatus: Parallex Flex (trademark) (Biotage, Inc)

Column: YMC Combiprep ODS-A 50×30 mm I.D.

Moving bed:

Solution A; 0.07 trifluoroacetic acid-acetonitrile

Solution B; 0.1% trifluoroacetic acid-H₂O

Gradient program: The mixture ratio of Solution A and Solution B wasinitially A:B=1:99, and the proportion of Solution A was increased 8.55%per 1 minute so that the ratio can be A:B=95:5 after 11 minutes.

Flow rate of the moving bed: 40 mL/min

TABLE 4 (IIIm)

Benzylation Obs MS Ex. X Y method Salt [M + 1] 20□ 2-F H C Free base332.5 21□ 3-F H C Free base 332.5 22□ 4-F H C Free base 332.5 23□ 2-C1 HA Hydrochloride 348.5 24□ 3-Cl H A Hydrochloride 348.5 25□ 4-Cl H AHydrochloride 348.5 26□ 2-Me H A Hydrochloride 328.3 27□ 3-Me H AHydrochloride 328.6 28□ 4-Me H A Hydrochloride 328.6 29□ 2-F 4-F C Freebase 350.2 30□ 2-Cl 4-F C Free base 366.2 31□ 2-Me 4-F C Free base 346.232□ 2-CN 4-F C Hydrochloride 357.4 33□ 2-F 5-F B Hydrochloride 350.7 34□2-F 5-Cl B Hydrochloride 366.1 35□ 2-F 5-Me B Hydrochloride 346.2 36□2-F 5-MeO B Hydrochloride 362.5 37□ 2-Cl 5-F B Hydrochloride 366.1 38□2-Cl 5-Cl B Hydrochloride 382.4 39□ 2-Cl 5-Me C Free base 362.5 40□ 2-Cl5-MeO C Free base 378.5

Example 201-{1-(Cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 7.43 (ddd, 1H, J=7.5, 7.5, 1.7 Hz), 7.39-7.30(m, 1H), 7.17 (ddd, 1H, J=7.5, 7.5, 1.1 Hz), 7.10 (ddd, 1H, J=9.7, 8.4,1.1 Hz), 5.60 (s, 1H), 5.12 (s, 2H), 3.74 (d, 2H, J=7.2 Hz), 3.67 (s,2H), 2.46 (s, 3H), 2.06 (brs, 1H), 1.92-1.75 (m, 1H), 1.75-1.51 (m, 5H),1.29-1.04 (m, 3H), 1.02-0.84 (m, 2H).

Example 211-{1-(Cyclohexylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ:7.36 (ddd, 1H, J=7.9, 7.9, 5.8 Hz), 7.18-7.00(m, 3H), 5.56 (s, 1H), 5.05 (s, 2H), 3.76 (d, 2H, J=7.3 Hz), 3.68 (s,2H), 2.46 (s, 3H), 1.94-1.76 (m, 1H), 1.75-1.54 (m, 5H), 1.30-1.05 (m,3H), 1.03-0.86 (m, 2H).

Example 221-{1-(Cyclohexylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ:7.36 (dd, 2H, J=8.8, 5.3 Hz), 7.09 (dd, 2H,J=8.8, 8.8 Hz), 5.56 (s, 1H), 5.01 (s, 2H), 3.73 (d, 2H, J=7.2 Hz), 3.67(s, 2H), 2.46 (s, 3H), 2.27 (brs, 1H), 1.92-1.75 (m, 1H), 1.75-1.52 (m,5H), 1.28-1.04 (m, 3H), 1.01-0.84 (m, 2H).

Example 231-{5-[(2-Chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.89 (2H, br dd, J=23.2, 12.0 Hz),1.06-1.15 (3H, m), 1.47 (2H, d, J=12.7 Hz), 1.60 (3H, t, J=10.4 Hz),1.71-1.74 (1H, m), 2.52 (3H, br s), 3.71 (2H, d, J=7.1 Hz), 3.96 (2H, brs), 5.21 (2H, s), 5.93 (1H, s), 7.38-7.45 (2H, m), 7.54 (1H, dd, J=7.3,1.5 Hz), 7.60 (1H, dd, J=6.8, 2.4 Hz), 8.92 (2H, s).

Example 241-{5-[(3-Chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.92 (2H, br q, J=11.5 Hz), 1.06-1.19 (3H,m), 1.49 (2H, d, J=12.4 Hz), 1.56-1.68 (3H, m), 1.69-1.79 (1H, m), 2.51(3H, br s), 3.75 (2H, d, J=7.1 Hz), 3.95 (2H, br s), 5.19 (2H, s), 5.89(1H, s), 7.42-7.46 (3H, m), 7.52 (1H, br s), 9.04 (2H, br s).

Example 251-{5-[(4-Chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.89 (2H, br dd, J=22.0, 12.2 Hz),1.05-1.18 (3H, m), 1.47 (2H, br d, J=11.5 Hz), 1.53-1.76 (4H, m), 2.51(3H, br s), 3.72 (2H, d, J=6.8 Hz), 3.95 (2H, br s), 5.15 (2H, s), 5.85(1H, s), 7.47 (4H, br d, J=1.0 Hz), 8.92 (2H, br s).

Example 261-{1-(Cyclohexylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (2H, br q, J=10.9 Hz), 1.03-1.19 (3H,m), 1.49 (2H, br d, J=13.2 Hz), 1.54-1.78 (4H, m), 2.35 (3H, s), 2.53(3H, br s), 3.71 (2H, d, J=7.2 Hz), 3.97 (2H, s), 5.15 (2H, s), 5.96(1H, s), 7.19-7.33 (3H, m), 7.40 (1H, br d, J=7.3 Hz), 9.01 (2H, br s).

Example 271-{1-(Cyclohexylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.92 (2H, br q, J=11.2 Hz), 1.08-1.21 (3H,m), 1.49 (2H, br d, J=13.2 Hz), 1.56-1.80 (4H, m), 2.32 (3H, s), 2.50(3H, br s), 3.73 (2H, d, J=7.2 Hz), 3.95 (2H, br t, J=5.0 Hz), 5.12 (2H,s), 5.87 (1H, s), 7.16-7.32 (4H, m), 8.97 (2H, br s).

Example 281-{1-(Cyclohexylmethyl)-5-[(4-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (2H, br dd, J=23.0, 11.6 Hz),1.05-1.17 (3H, m), 1.48 (2H, br d, J=12.7 Hz), 1.55-1.75 (4H, m), 2.31(3H, s), 2.51 (3H, br s), 3.71 (2H, d, J=7.1 Hz), 3.95 (2H, br s), 5.10(2H, s), 5.89 (1H, s), 7.22 (2H, d, J=7.8 Hz), 7.33 (2H, d, J=8.0 Hz),9.01 (2H, br s).

Example 291-{1-(Cyclohexylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.83-1.02 (2H, m), 1.05-1.29 (3H, m),1.49-1.91 (6H, m), 2.46 (3H, s), 3.66 (2H, s), 3.72 (2H, d, J=7.3 Hz),5.06 (2H, s), 5.57 (1H, s), 6.80-6.96 (2H, m), 7.34-7.46 (1H, m).

Example 301-{5-[(2-Chloro-4-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.87-1.01 (2H, m), 1.07-1.28 (3H, m),1.53-1.94 (6H, m), 2.48 (3H, s), 3.69 (2H, s), 3.75 (2H, d, J=7.3 Hz),5.10 (2H, s), 5.60 (1H, s), 7.00-7.07 (1H, m), 7.16-7.1 (1H, m),7.42-7.48 (1H, m).

Example 311-{1-(Cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.84-0.99 (2H, m), 1.05-1.27 (3H, m),1.50-1.90 (6H, m), 2.36 (3H, s), 2.48 (3H, s), 3.67 (2H, s), 3.71 (2H,d, J=7.3 Hz), 4.98 (2H, s), 5.58 (1H, s), 6.87-6.99 (2H, m), 7.28-7.34(1H, m).

Example 322-[({1-(Cyclohexylmethyl)-3-[(methylamino)methyl]-1H-pyrazol-5-yl}oxy)methyl]-5-fluorobenzonitrilehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.77-1.00 (2H, m), 1.01-1.22 (3H, m),1.41-1.53 (2H, m), 1.53-1.68 (3H, m), 1.68-1.82 (1H, m), 2.54 (3H, t,J=5.3 Hz), 3.73 (2H, d, J=7.0 Hz), 3.98 (2H, t, J=5.7 Hz), 5.30 (2H, s),5.97 (1H, s), 7.68 (1H, ddd, J=8.6, 8.6, 2.8 Hz), 7.83 (1H, dd, J=8.6,5.5 Hz), 8.00 (1H, dd, J=8.6, 2.8 Hz), 8.95 (2H, brs).

Example 331-{1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.80-0.98 (2H, m), 1.03-1.21 (3H, m),1.42-1.52 (2H, m), 1.54-1.80 (4H, m), 2.52 (3H, t, J=5.3 Hz), 3.72 (2H,d, J=7.2 Hz), 3.97 (2H, t, J=5.6 Hz), 5.20 (2H, s), 5.96 (1H, s),7.26-7.48 (3H, m), 9.03 (2H, brs).

Example 341-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.81-1.00 (2H, m), 1.04-1.22 (3H, m),1.41-1.53 (2H, m), 1.54-1.80 (4H, m), 2.52-2.56 (3H, m), 3.72 (2H, d,J=7.2 Hz), 3.94-4.03 (2H, m), 5.22 (2H, s), 5.93 (1H, s), 7.36 (1H, t,J=9.2 Hz), 7.49-7.57 (1H, m), 7.62-7.68 (1H, m), 8.92 (2H, br s).

Example 351-{1-(Cyclohexylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.79-0.99 (2H, m), 1.02-1.21 (3H, m),1.40-1.52 (2H, m), 1.52-1.79 (4H, m), 2.29 (3H, s), 2.53 (3H, brs), 3.70(2H, d, J=7.0 Hz), 3.96 (2H, t, J=5.5 Hz), 5.15 (2H, s), 5.96 (1H, s),7.15 (1H, dd, J=10.0, 8.5 Hz), 7.21-7.28 (1H, m), 7.35 (1H, dd, J=7.2,1.8 Hz), 9.06 (2H, brs).

Example 361-{1-(Cyclohexylmethyl)-5-[(2-fluoro-5-methoxybenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.83-0.97 (2H, m), 1.03-1.19 (3H, m),1.43-1.52 (2H, m), 1.53-1.78 (4H, m), 2.53 (3H, brs), 3.71 (2H, d, J=7.1Hz), 3.75 (3H, s), 3.97 (2H, t, J=5.6 Hz), 5.17 (2H, s), 5.94 (1H, s),6.98 (1H, ddd, J=8.9, 8.9, 3.7 Hz), 7.09 (1H, dd, J=6.0, 3.3 Hz), 7.21(1H, dd, J=9.3, 9.3 Hz), 8.99 (2H, brs).

Example 371-{5-[(2-Chloro-5-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.84-1.01 (2H, m), 1.04-1.22 (3H, m),1.43-1.54 (2H, m), 1.55-1.83 (4H, m), 2.53 (3H, brs), 3.75 (2H, d, J=7.2Hz), 3.97 (2H, t, J=5.0 Hz), 5.22 (2H, s), 5.95 (1H, s), 7.33 (1H, ddd,J=8.5, 8.5, 3.0 Hz), 7.49 (1H, dd, J=9.1, 3.0 Hz), 7.61 (1H, dd, J=8.9,5.0 Hz), 8.97 (2H, brs).

Example 381-{1-(Cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.83-1.00 (2H, m), 1.05-1.22 (3H, m),1.43-1.54 (2H, m), 1.54-1.83 (4H, m), 2.53 (3H, brs), 3.74 (2H, d, J=7.2Hz), 3.98 (2H, t, J=5.6 Hz), 5.22 (2H, s), 5.95 (1H, s), 7.52 (1H, dd,J=8.6, 2.6 Hz), 7.60 (1H, d, J=8.6 Hz), 7.68 (1H, d, J=2.6 Hz), 8.98(2H, brs).

Example 391-{5-[(2-Chloro-5-methylbenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 7.28 (d, 1H, J=8.3 Hz), 7.26 (s, 1H), 7.10(dd, 1H, J=8.3, 1.7 Hz), 5.59 (s, 1H), 5.11 (s, 2H), 3.77 (d, 2H, J=7.3Hz), 3.68 (s, 2H), 2.47 (s, 3H), 2.34 (s, 3H), 1.99 (brs, 1H), 1.96-1.80(m, 1H), 1.75-1.55 (m, 5H), 1.29-1.05 (m, 3H), 1.05-0.88 (m, 2H).

Example 401-{5-[(2-Chloro-5-methylbenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.91-1.02 (2H, m), 1.08-1.27 (3H, m),1.59-1.74 (5H, m), 1.82-1.95 (1H, m), 2.46 (3H, s), 3.65 (2H, s), 3.78(2H, d, J=7.3 Hz), 3.80 (3H, s), 5.11 (2H, s), 5.56 (1H, s), 6.83 (1H,dd, J=8.8, 3.1 Hz), 7.02 (1H, d, J=3.1 Hz), 7.30 (1H, d, J=8.8 Hz).

Examples 41 to 91

The compounds of Examples 41 to 91 as shown in Table 5 were prepared inthe same manner as in Examples 20 to 40 by using the compound obtainedin Reference Example 4 and a corresponding benzyl bromide or benzylchloride.

TABLE 5

Benzylation Obs MS Ex. X Y method Salt [M + 1] 41□ 2-MeO H AHydrochloride 344.3 42□ 3-MeO H A Hydrochloride 344.3 43□ 4-MeO H AHydrochloride 344.3 44□ 2-CF₃ H A Hydrochloride 382.4 45□ 3-CF₃ H AHydrochloride 382.4 46□ 4-CF₃ H A Hydrochloride 382.4 47□ 2-CN H CHydrochloride 339.2 48□ 3-CN H C Free base 339.2 49□ 4-CN H C Free base339.2 50□ 2-F 3-F B Hydrochloride 350.4 51□ 2-F 3-Cl B Hydrochloride366.1 52□ 2-F 3-Me B Hydrochloride 346.5 53□ 2-F 3-MeO B Hydrochloride362.5 54□ 2-Cl 3-F B Hydrochloride 366.1 55□ 2-Cl 3-Cl C Free base 382.456□ 2-Cl 3-Me B Hydrochloride 362.2 57□ 2-Cl 3-MeO B Hydrochloride 378.558□ 2-Me 3-F B Hydrochloride 346.2 59□ 2-Me 3-Cl B Hydrochloride 362.260□ 2-Me 3-Me B Hydrochloride 342.3 61□ 2-MeO 3-F B Hydrochloride 362.562□ 2-MeO 3-Cl B Hydrochloride 378.5 63□ 2-Me 5-F B Hydrochloride 346.264□ 2-Me 5-Cl C Free base 362.2 65□ 2-Me 5-Me C Free base 342.3 66□2-MeO 5-F B Hydrochloride 362.2 67□ 2-MeO 5-Cl C Free base 378.5 68□ 2-F5-CN C Free base 357.2 69□ 2-CN 5-F C Free base 357.4 70□ 2-F 6-F BHydrochloride 350.4 71□ 2-F 6-Cl C Free base 367.5 72□ 2-Cl 6-Cl BHydrochloride 382.4 73□ 2-Me 6-F C Free base 346.5 74□ 2-Me 6-Cl C Freebase 362.2 75□ 2-Me 6-Me C Hydrochloride 342.3 76□ 2-MeO 6-F BHydrochloride 363.6 77□ 2-MeO 6-Cl B Hydrochloride 378.5 78□ 3-F 4-F CFree base 350.4 79□ 3-Cl 4-F C Free base 342.3 80□ 3-Me 4-F C Free base346.2 81□ 3-MeO 4-F C Free base 362.5 82□ 3-CN 4-F C Free base 357.4 83□3-F 5-F C Free base 350.2 84□ 3-F 5-Cl C Free base 367.0 85□ 3-Cl 5-Cl CFree base 384.3 86□ 3-Me 5-F C Free base 346.5 87□ 3-Me 5-Cl BHydrochloride 362.2 88□ 3-Me 5-Me C Free base 342.3 89□ 3-MeO 5-F C Freebase 362.2 90□ 3-MeO 5-Cl C Free base 378.5 91□ 3-MeO 5-MeO C Free base374.3

Examples 92 to 114

The compounds of Examples 92 to 114 as shown in Table 6 were prepared inthe same manner as in Examples 20 to 40 except that the compoundobtained in Reference Example 5 and a corresponding benzyl bromide orbenzyl chloride were used.

TABLE 6

Benzylation Obs MS Ex. X Y method Salt [M + 1]  92□ 2-F H C Free base334.5  93□ 3-F H C Free base 334.5  94□ 4-F H C Free base 334.5  95□2-Cl H A Hydrochloride 350.4  96□ 3-Cl H A Hydrochloride 350.4  97□ 4-ClH A Hydrochloride 350.4  98□ 2-Br H A Free base 394.1  99□ 3-Br H A Freebase 394.1 100□ 2-Me H A Hydrochloride 330.3 101□ 3-Me H A Hydrochloride330.3 102□ 4-Me H A Hydrochloride 330.3 103□ 2-CF₃ H A Hydrochloride384.3 104□ 3-CF₃ H A Hydrochloride 384.3 105□ 4-CF₃ H A Hydrochloride384.3 106□ 2-F 4-F C Free base 352.1 107□ 2-Cl 4-F C Free base 368.1108□ 2-Me 4-F C Free base 348.2 109□ 2-F 5-F C Free base 352.1 110□ 2-F5-Cl C Free base 368.1 111□ 2-F 5-Me C Free base 348.2 112□ 2-Cl 5-F CHydrochloride 368.4 113□ 2-Cl 5-Cl C Hydrochloride 384.3 114□ 2-Cl 5-MeC Free base 364.2

Examples 115 to 134

The compounds of Examples 115 to 134 as shown in Table 7 were preparedin the same manner as in Examples 20 to 40 except that the compoundobtained in Reference Example 2, 3 or 9 to 13 and a corresponding benzylbromide or benzyl chloride were used.

TABLE 7

Benzylation Obs MS Ex . Q X Y method [M + 1] 115□

H H B 326.4 116□

3-Cl H B 360.5 117□

2-F 5-F B 362.5 118□

2-F 5-Cl B 378.5 119□

H H C 328.3 120□

3-Cl H C 362.5 121□

2-F 5-Cl C 380.4 122□

3-Cl H C 376.5 123□

H H C 350.4 124□

2-F 5-F C 386.6 125□

2-F 5-Cl C 402.5 126□

H H C 332.5 127□

2-F 5-F C 368.4 128□

2-F 5-Cl C 384.3 129□

H H C 272.3 130□

2-F 5-F C 308.4 131□

2-F 5-Cl C 324.4 132□

H H C 286.3 133□

2-F 5-F C 322.4 134□

2-F 5-Cl C 338.4 (* shows the bonding position)

Example 1291-[5-(Benzyloxy)-1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.28-0.34 (2H, m), 0.47-0.54 (2H, m),1.15-1.27 (1H, m), 2.63 (3H, br s), 3.81 (2H, d, J=7.0 Hz), 4.09 (2H, brs), 5.09 (2H, s), 6.11 (1H, s), 7.35-7.42 (5H, m), 9.77 (2H, br s).

Example 1301-{1-(Cyclopropylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.28-0.34 (2H, m), 0.49-0.55 (2H, m),1.15-1.28 (1H, m), 2.64 (3H, br s), 3.81 (2H, d, J=7.0 Hz), 4.10 (2H, brs), 5.12 (2H, s), 6.14 (1H, s), 7.02-7.10 (2H, m), 7.11-7.18 (1H, m),9.78 (2H, br s).

Example 1311-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(cyclopropylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.28-0.35 (2H, m), 0.48-0.56 (2H, m),1.14-1.27 (1H, m), 2.64 (3H, br s), 3.81 (2H, d, J=7.0 Hz), 4.10 (2H, brs), 5.11 (2H, s), 6.15 (1H, s), 7.06 (1H, br t, J=9.0 Hz), 7.32 (1H, brddd, J=8.7, 4.5, 2.7 Hz), 7.41 (1H, br dd, J=6.1, 2.7 Hz), 9.79 (2H, brs).

Example 1321-[5-(Benzyloxy)-1-(cyclobutylmethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.67-1.84 (4H, m), 1.86-1.95 (2H, m), 2.50(3H, br s), 2.59-2.72 (1H, m), 3.91 (2H, br d, J=7.2 Hz), 3.93 (2H, brt, J=5.6 Hz), 5.14 (2H, s), 5.91 (1H, s), 7.33-7.48 (5H, m), 9.10 (2H,br s).

Example 1331-{1-(Cyclobutylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.70-1.92 (4H, m), 1.92-2.06 (2H, m), 2.61(3H, br s), 2.73 (1H, br td, J=14.8, 7.3 Hz), 3.95 (2H, d, J=7.3 Hz),4.09 (2H, br s), 5.11 (2H, s), 6.13 (1H, s), 7.01-7.11 (2H, m),7.11-7.19 (1H, m), 9.79 (2H, s).

Example 1341-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(cyclobutylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.70-1.92 (4H, m), 1.94-2.04 (2H, m), 2.61(3H, br s), 2.69-2.78 (1H, m), 3.95 (2H, d, J=7.2 Hz), 4.09 (2H, br s),5.10 (2H, s), 6.13 (1H, s), 7.06 (1H, t, J=9.0 Hz), 7.33 (1H, ddd,J=8.8, 4.5, 2.7 Hz), 7.42 (1H, dd, J=6.2, 2.6 Hz), 9.79 (2H, br s).

Examples 135 to 191

The compounds of Examples 135 to 191 as shown in Table 8 were preparedin the same manner as in Examples 20 to 40 except that the Compound(IIIa) in Reference Example 1 and a corresponding benzyl bromide orbenzyl chloride were used.

TABLE 8

Benzylation Obs MS Ex. X Y method Salt [M + 1] 135□ 2-F H C TFA salt317.9 136□ 3-F H A Hydrochloride 318.2 137□ 4-F H C TFA salt 318.0 138□2-Cl H C TFA salt 333.9 139□ 3-Cl H A Hydrochloride 334.2 140□ 4-Cl H CFree base 333.9 141□ 2-Me H C TFA salt 313.9 142□ 3-Me H A Hydrochloride314.3 143□ 4-Me H C TFA salt 313.9 144□ 2-F 4-F C TFA salt 335.9 145□2-Cl 4-F C TFA salt 351.8 146□ 2-Me 4-F C TFA salt 331.8 147□ 2-F 5-F BHydrochloride 336.4 148□ 2-F 5-Cl B Hydrochloride 352.4 149□ 2-F 5-Me CTFA salt 331.9 150□ 2-Cl 5-F C TFA salt 351.9 151□ 2-Cl 5-Cl C TFA salt367.7 152□ 2-Cl 5-Me C TFA salt 348.1 153□ 2-Br H C TFA salt 379.6 154□3-Br H C TFA salt 377.8 155□ 4-Br H C Free base 379.6 156□ 2-CF₃ H C TFAsalt 367.8 157□ 3-CF₃ H C TFA salt 367.8 158□ 4-CF₃ H C Free base 368.2159□ 2-CF₃O H C TFA salt 383.7 160□ 3-CF₃O H C TFA salt 383.8 161□4-CF₃O H C TFA salt 383.8 162□ 2-CN H C TFA salt 324.8 163□ 3-CN H C TFAsalt 324.8 164□ 4-CN H C TFA salt 325.1 165□ 2-F 3-F C TFA salt 335.9166□ 2-F 3-Cl C Free base 351.9 167□ 2-F 3-Me C TFA salt 331.9 168□ 2-Cl3-F C TFA salt 351.8 169□ 2-Cl 3-Cl C TFA salt 367.8 170□ 2-Cl 3-Me CTFA salt 348.0 171□ 2-Me 3-F C TFA salt 331.9 172□ 2-Me 3-Cl C TFA salt348.0 173□ 2-Me 3-Me C TFA salt 328.1 174□ 2-Me 5-F C TFA salt 332.1175□ 2-Me 5-Cl C TFA salt 348.0 176□ 2-Me 5-Me C TFA salt 328.1 177□ 2-F6-F C TFA salt 335.9 178□ 2-F 6-Cl C TFA salt 351.9 179□ 2-Cl 6-Cl C TFAsalt 367.7 180□ 2-Me 6-F C TFA salt 332.0 181□ 2-Me 6-Cl C TFA salt347.8 182□ 2-Me 6-Me C TFA salt 327.9 183□ 3-F 4-F C TFA salt 335.7 184□3-Cl 4-F C Free base 351.9 185□ 3-Me 4-F C TFA salt 331.8 186□ 3-F 5-F CTFA salt 336.1 187□ 3-F 5-Cl C TFA salt 352.0 188□ 3-Cl 5-Cl C TFA salt368.0 189□ 3-Me 5-F C TFA salt 332.0 190□ 3-Me 5-Cl C TFA salt 348.0191□ 3-Me 5-Me C TFA salt 328.0

Example 1351-{1-(Cyclopentylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.11-1.26 (2H, m), 1.46-1.68 (6H, m),2.24-2.37 (1H, m), 2.70 (3H, s), 3.86 (2H, d, J=7.6 Hz), 4.14 (2H, s),5.15 (2H, s), 5.91 (1H, s), 7.10 (1H, dd, J=9.2, 9.2 Hz), 7.17 (1H, dd,J=7.6, 7.6 Hz), 7.33-7.44 (2H, m), 9.15 (2H, brs).

Example 1361-{1-(Cyclopentylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.16-1.27 (2H, m), 1.44-1.61 (6H, m),2.22-2.34 (1H, m), 2.51 (3H, s), 3.82 (2H, d, J=7.5 Hz), 3.95 (2H, br t,J=5.7 Hz), 5.18 (2H, s), 5.85 (1H, s), 7.19 (1H, ddt, J=12.5, 6.9, 2.3Hz), 7.26-7.31 (2H, m), 7.42-7.50 (1H, m), 8.94 (2H, br s).

Example 1371-{1-(Cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.12-1.28 (2H, m), 1.44-1.70 (6H, m),2.25-2.39 (1H, m), 2.67 (3H, s), 3.86 (2H, d, J=7.6 Hz), 4.10 (2H, s),5.03 (2H, s), 5.85 (1H, s), 7.08 (2H, dd, J=8.8, 8.8 Hz), 7.35 (2H, dd,J=8.8, 3.2 Hz), 9.58 (2H, brs).

Example 1381-{5-[(2-Chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.13-1.30 (2H, m), 1.44-1.71 (6H, m),2.27-2.40 (1H, m), 2.68 (3H, s), 3.88 (2H, d, J=7.6 Hz), 4.12 (2H, s),5.16 (2H, s), 5.90 (1H, s), 7.24-7.37 (2H, m), 7.38-7.48 (2H, m), 9.42(2H, brs).

Example 1391-{5-[(3-Chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.17-1.27 (2H, m), 1.44-1.61 (6H, m),2.25-2.34 (1H, m), 2.51 (3H, br s), 3.82 (2H, d, J=7.5 Hz), 3.96 (2H, brt, J=5.7 Hz), 5.18 (2H, s), 5.84 (1H, s), 7.39-7.45 (3H, m), 7.51 (1H,br s), 8.89 (2H, br s).

Example 1401-{5-[(4-Chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 1.11-1.29 (2H, m), 1.40-1.68 (6H, m),2.26-2.42 (1H, m), 2.58 (3H, s), 3.82 (2H, d, J=7.6 Hz), 4.03 (2H, s),5.03 (2H, s), 6.02 (1H, s), 7.32 (2H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4Hz).

Example 1411-{1-(Cyclopentylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.11-1.28 (2H, m), 1.46-1.71 (6H, m),2.25-2.43 (1H, m), 2.34 (3H, s), 2.72 (3H, s), 3.88 (2H, d, J=7.6 Hz),4.16 (2H, s), 5.09 (2H, s), 5.93 (1H, s), 7.17-7.37 (4H, m), 9.23 (2H,brs).

Example 1421-{1-(Cyclopentylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.17-1.27 (2H, m), 1.44-1.61 (6H, m),2.24-2.34 (4H, m), 2.51 (3H, s), 3.80 (2H, d, J=7.3 Hz), 3.95 (2H, br t,J=5.7 Hz), 5.11 (2H, s), 5.86 (1H, s), 7.15-7.31 (4H, m), 8.95 (2H, brs).

Example 1431-{1-(Cyclopentylmethyl)-5-[(4-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.11-1.27 (2H, m), 1.44-1.71 (6H, m),2.25-2.42 (1H, m), 2.34 (3H, s), 2.70 (3H, s), 3.88 (2H, d, J=7.6 Hz),4.13 (2H, s), 5.05 (2H, s), 5.87 (1H, s), 7.20 (2H, d, J=7.8 Hz), 7.26(2H, d, J=7.8 Hz), 9.18 (2H, brs).

Example 1441-{1-(Cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.04-1.22 (2H, m), 1.36-1.60 (6H, m),2.17-2.32 (1H, m), 2.59 (3H, s), 3.76 (2H, d, J=6.8 Hz), 4.01 (2H, s),5.00 (2H, s), 5.80 (1H, s), 6.76-6.90 (2H, m), 7.32 (1H, dd, J=14.4, 8.4Hz), 9.36 (2H, brs).

Example 1451-{5-[(2-Chloro-4-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.07-1.23 (2H, m), 1.38-1.63 (6H, m),2.21-2.35 (1H, m), 2.59 (3H, s), 3.78 (2H, d, J=7.6 Hz), 4.01 (2H, s),5.04 (2H, s), 5.79 (1H, s), 6.96 (1H, ddd, J=8.6, 8.6, 2.6 Hz), 7.12(1H, dd, J=8.6, 2.6 Hz), 7.36 (1H, dd, J=8.6, 6.0 Hz), 9.43 (2H, brs).

Example 1461-{1-(Cyclopentylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.05-1.23 (2H, m), 1.37-1.61 (6H, m),2.20-2.37 (1H, m), 2.27 (3H, s), 2.57 (3H, s), 3.75 (2H, d, J=7.6 Hz),3.99 (2H, s), 4.93 (2H, s), 5.78 (1H, s), 6.78-6.91 (2H, m), 7.23 (1H,dd, J=8.4, 6.0 Hz), 9.46 (2H, brs).

Example 1471-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.10-1.30 (2H, m), 1.45-1.72 (6H, m),2.20-2.35 (1H, m), 2.51 (3H, t, J=5.5 Hz), 3.79 (2H, d, J=7.3 Hz), 3.96(2H, t, J=5.7 Hz), 5.19 (2H, s), 5.94 (1H, s), 7.24-7.48 (3H, m), 9.00(2H, br s).

Example 1481-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.15-1.27 (2H, m), 1.46-1.59 (6H, m), 2.27(1H, q, J=7.0 Hz), 2.54 (3H, br t, J=5.6 Hz), 3.80 (2H, d, J=7.5 Hz),3.99 (2H, t, J=5.5 Hz), 5.22 (2H, s), 5.91 (1H, s), 7.36 (1H, t, J=9.2Hz), 7.51-7.56 (1H, m), 7.65 (1H, dd, J=6.5, 2.7 Hz), 8.81 (2H, br s).

Example 1491-{1-(Cyclopentylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 1.10-1.30 (2H, m), 1.42-1.71 (6H, m),2.20-2.42 (1H, m), 2.32 (3H, s), 2.67 (3H, s), 3.85 (2H, d, J=7.8 Hz),4.10 (2H, s), 5.08 (2H, s), 5.88 (1H, s), 6.97 (1H, dd, J=9.6, 9.6 Hz),7.11-7.23 (2H, m), 9.30 (2H, brs).

Example 1501-{5-[(2-Chloro-5-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 1.12-1.33 (2H, m), 1.43-1.71 (6H, m),2.27-2.45 (1H, m), 2.61 (3H, s), 3.87 (2H, d, J=7.5 Hz), 4.10 (2H, s),5.10 (2H, s), 5.81 (1H, s), 7.00 (1H, ddd, J=8.5, 8.5, 3.0 Hz), 7.16(1H, dd, J=9.0, 3.0 Hz), 7.36 (1H, dd, J=8.5, 4.8 Hz), 9.55 (2H, brs).

Example 1511-{1-(Cyclopentylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 1.11-1.33 (2H, m), 1.40-1.72 (6H, m),2.27-2.45 (1H, m), 2.60 (3H, s), 3.86 (2H, d, J=7.5 Hz), 4.03 (2H, s),5.08 (2H, s), 5.83 (1H, s), 7.26 (1H, dd, J=8.4, 2.2 Hz), 7.33 (1H, d,J=8.4 Hz), 7.42 (1H, d, J=2.2 Hz), 9.57 (2H, brs).

Example 1521-{5-[(2-Chloro-5-methylbenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (400 MHz, CDCl₃) δ: 1.16-1.31 (2H, m), 1.50-1.73 (6H, m),2.28-2.43 (1H, m), 2.33 (3H, s), 2.72 (3H, s), 3.89 (2H, d, J=7.6 Hz),4.13 (2H, s), 5.04 (2H, s), 5.87 (1H, s), 7.18 (1H, d, J=8.0 Hz), 7.27(1H, dd, J=8.0, 2.0 Hz), 7.35 (1H, d, J=2.0 Hz), 9.33 (2H, brs).

Example 1921-[5-(Benzyloxy)-1-(2-cyclopentylethyl)-1H-pyrazol-3-yl]-N-methylmethanamine

The title compound was prepared in the same manner as in Examples 20 to40 except that the compound obtained in Reference Example 14 was used.The benzylation reaction of Step (i) was carried out by Method Bdescribed as a general process in Examples 20 to 40.

¹H-NMR (300 MHz, CDCl₃) δ: 1.09 (2H, m), 1.41-1.89 (9H, m), 2.67 (3H,s), 4.04 (2H, t, J=7.2 Hz), 4.20 (2H, s), 5.17 (2H, s), 6.43 (1H, s),7.42-7.39 (5H, m), 10.06 (2H, s).

Obs MS [M+1]: 314.3

Example 1931-{1-(2-Cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

The title compound was prepared in the same manner as in Example 192.

¹H-NMR (300 MHz, CDCl₃) δ: 1.07 (2H, m), 1.42-1.84 (9H, m), 2.63 (3H, brs), 3.96 (2H, t, J=7.2 Hz), 4.11 (2H, br s), 5.13 (2H, s), 6.20 (1H, s),7.05 (2H, m), 7.15 (1H, m), 9.85 (2H, br s).

Obs MS [M+1]: 350.4

Example 1941-{1-(2-Cyclopentylethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

The title compound was prepared in the same manner as in Example 192.

¹H-NMR (300 MHz, CDCl₃) δ: 1.07 (2H, s), 1.37-1.80 (7H, m), 1.88 (2H,m), 2.78 (3H, s), 4.15 (2H, t, J=7.2 Hz), 4.40 (2H, s), 5.30 (2H, s),6.92 (3H, m), 7.49 (1H, dd, J=14.7, 8.4 Hz), 10.38 (2H, br s).

Obs MS [M+1]: 350.4

Examples 195 to 197

The compounds of Examples 195 to 197 as shown in Table 9 were preparedin the same manner as in Examples 20 to 40 except that the compoundobtained in Reference Example 36 and a corresponding benzyl bromide wereused. The benzylation reaction of Step (i) was carried out by Method Bdescribed as a general process in Examples 20 to 40.

TABLE 9

Ex. X Obs MS [M + 1] 195□ 2-F 326.4 196□ 3-F 326.4 197□ 4-F 326.4

Example 1981-[5-(Benzyloxy)-1-(2-fluorobenzyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

Step (i)

A solution of 2-fluorobenzylbromide (2.0 g, 11 mmol) and hydrazinemonohydrate (3.1 mL, 63 mmol) in ethanol (10 mL) was stirred at 60° C.for 18 hours. The solvent was evaporated under reduced pressure, and theconcentrated residue was diluted with chloroform (40 mL) and washed withwater (6 mL) twice. The organic layer was dried over anhydrous MgSO₄,and the solvent was evaporated under reduced pressure. The concentratedresidue was dissolved in chloroform (6 mL), to the solution was added 4mol/L HCl/1,4-dioxane (12 mL) at room temperature, the solution wasstirred at room temperature for 30 minutes, and the solvent wasevaporated under reduced pressure. To the concentrated residue was addeda mixed solution of ethyl acetate: n-hexane (2:1) (20 mL), the mixturewas suspended, and the resulting precipitate was collected by filtrationand dried under reduced pressure to give Compound (In) (1.68 g, 75%).

Step (ii)

A solution of the Compound (In) (1.0 g, 4.7 mmol), the Compound (IIa)prepared in Step (i) of Reference Example 1 (1.22 g, 4.7 mmol) andtriethylamine (1.6 mL, 11 mmol) in ethanol (9 mL) was stirred at 80° C.for 5 hours. The reaction mixture was cooled to room temperature, to theconcentrated residue was added 5% aq. KHSO₄, and the mixture wasextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over anhydrous MgSO₄, and the solvent wasevaporated under reduced pressure. The concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=50:50) togive Compound (IIIn) (970 mg, 62%) as a light-brown oil.

Steps (iii) to (iv)

To a solution of the Compound (IIIn) (100 mg, 0.30 mmol) and cesiumcarbonate (146 mg, 0.45 mmol) in acetonitrile (1.5 mL) was added benzylchloride (41 mg, 0.33 mmol) at room temperature, and the reactionmixture was stirred at room temperature for 17 hours. The reactionmixture was diluted with ethyl acetate, the salt was filtered off, andthe filtrate was evaporated under reduced pressure to give aconcentrated residue, which was used in the next step without furtherpurification. The residue was dissolved in chloroform (1 mL), to thesolution was added 4 mol/L HCl/1,4-dioxane (4 mL) at room temperature,the solution was stirred at room temperature for 30 minutes, and thesolvent was evaporated under reduced pressure. To the concentratedresidue was added a mixed solution of ethyl acetate: n-hexane (5:1), themixture was suspended, and the resulting precipitate was collected byfiltration and dried under reduced pressure to give the title compound(62 mg, 59% yield in 2 steps) as a light brown powder.

Obs MS [M+1]: 350.4

Examples 199 to 240

The compounds of Examples 199 to 240 as shown in Table 10 were preparedin the same manner as in Example 198 except that a corresponding benzylchloride or benzyl bromide was used.

TABLE 10

Obs MS Ex. X Y Z [M + 1] 199□ H H 3′-F 326.2 200□ H H 4′-F 326.2 201□ HH 2′-Cl 342.3 202□ H H 3′-Cl 342.3 203□ H H 4′-Cl 342.3 204□ H H 2′-Me322.2 205□ H H 3′-Me 322.2 206□ H H 4′-Me 322.2 207□ H H 2′-CF₃ 376.5208□ H H 4′-CF₃ 376.5 209□ H H 2′-CN 333.4 210□ H H 3′-CN 333.4 211□ H H4′-CN 333.4 212□ H H 4′-MeO 338.4 213□ H H 2′-CF₃O 392.2 214□ H H3′-CF₃O 392.2 215□ H H 4′-CF₃O 392.2 216□ 2-F H 2′-F 344.1 217□ 2-F 5-F2′-F 362.1 218□ 2-F H 4′-F 344.1 219□ 2-F 5-F 4′-F 362.1 220□ 2-F H2′-Cl 360.3 221□ 2-F 5-F 2′-Cl 378.5 222□ 2-F H 4′-Cl 360.3 223□ 3-Me H4′-Cl 356.3 224□ 2-F 5-F 4′-Cl 378.5 225□ 2-F 5-Me 4′-Cl 374.3 226□ 2-FH 2′-Me 340.4 227□ 2-F 5-F 2′-Me 358.6 228□ 2-F H 4′-Me 340.4 229□ 3-MeH 4′-Me 336.4 230□ 2-F 5-F 4′-Me 358.3 231□ 2-F 5-Me 4′-Me 354.4 232□2-F H 2′-CN 351.6 233□ 4-F H 2′-CN 351.6 234□ 2-F 5-F 2′-CN 369.2 235□2-F 5-Cl 2′-CN 385.2 236□ 2-F 5-Me 2′-CN 365.3 237□ 2-F 5-F 4′-CN 369.2238□ 2-F 5-Cl 4′-CN 385.2 239□ 2-F H 4′-CF₃O 410.4 240□ 2-F 5-F 4′-CF₃O428.3

Examples 241 to 275

The compounds of Examples 241 to 275 as shown in Table 11 were preparedin the same manner as in Examples 20 to 40 except that the compoundobtained in Reference Examples 15 to 26 and a corresponding benzylchloride or benzyl bromide were used. The benzylation in Step (i) wascarried out by Method B or C described as a general process in Examples20 to 40.

TABLE 11

Benzylation Ex. R X Y method 241□ n-Bu H H C 242□ n-Bu 2-F 5-F C 243□n-Pent H H C 244□ n-Pent 2-F 5-F C 245□ n-Hex H H C 246□ n-Hex 2-F 5-F C247□ n-Hex 2-F 5-Cl C 248□ n-Hep H H C 249□ n-Hep 2-F 5-F C 250□

H H C 251□

2-F 5-F C 252□

2-F 4-F C 253□

2-Cl 4-F C 254□

H H C 255□

2-F 5-F C 256□

2-F 5-Cl C 257□

H H C 258□

2-F 5-F C 259□

2-F 5-Cl C 260□

H H B 261□

3-Cl H C 262□

2-F 5-F C 263□

2-F 5-Cl C 264□

H H B 265□

3-Cl H C 266□

2-F 5-F C 267□

2-F 5-Cl C 268□

H H C 269□

2-F 5-F C 270□

2-F 5-Cl C 271□

H H C 272□

2-F 5-F C 273□

H H C 274□

2-F 5-F C 275□

2-F 5-Cl C (*shows the bonding position)

Example 241

Obs MS [M+1]: 274.5

Example 242

Obs MS [M+1]: 310.4

Example 243

Obs MS [M+1]: 288.3

Example 244

Obs MS [M+1]: 324.4

Example 245

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.77-0.84 (3H, m), 1.14-1.25 (6H, m),1.59-1.69 (2H, m), 2.53 (3H, br t, J=5.3 Hz), 3.88 (2H, br t, J=7.0 Hz),3.96 (2H, br t, J=5.9 Hz), 5.16 (2H, s), 5.85 (1H, s), 7.35-7.47 (5H,m), 8.84 (2H, br s).

Obs MS [M+1]: 302.5

Example 246

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.76-0.83 (3H, m), 1.12-1.23 (6H, m),1.57-1.68 (2H, m), 2.53 (3H, br t, J=5.3 Hz), 3.87 (2H, br t, J=6.8 Hz),3.97 (2H, br t, J=5.5 Hz), 5.20 (2H, s), 5.92 (1H, s), 7.26-7.39 (2H,m), 7.40-7.47 (1H, m), 8.91 (2H, br s).

Obs MS [M+1]: 338.4

Example 247

¹H-NMR (300 MHz, DMSO-d₆) 5:0.75-0.83 (3H, m), 1.10-1.24 (6H, m),1.57-1.68 (2H, m), 2.52 (3H, br s), 3.86 (4H, br t, J=6.8 Hz), 3.97 (4H,br s), 5.20 (2H, s), 5.92 (1H, s), 7.35 (1H, t, J=9.2 Hz), 7.49-7.56(1H, m), 7.65 (1H, dd, J=6.2, 2.6 Hz), 8.90 (2H, br s).

Obs MS [M+1]: 354.5

Example 248

Obs MS [M+1]: 316.6

Example 249

Obs MS [M+1]: 352.4

Example 250

¹H-NMR (300 MHz, CDCl₃) δ: 0.73 (6H, t, J=7.3 Hz), 1.75 (2H, m), 1.88(2H, m), 2.62 (3H, s), 4.06 (1H, m), 4.17 (2H, s), 5.13 (2H, s), 6.25(1H, s), 7.39 (5H, m), 9.89 (2H, br s).

Example 251

Obs MS [M+1]: 324.4

Example 252

Obs MS [M+1]: 324.7

Example 253

Obs MS [M+1]: 340.4

Example 2541-[5-(Benzyloxy)-1-(2-methylpropyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.82 (6H, d, J=6.8 Hz), 1.98-2.09 (1H, m),2.52 (3H, br s), 3.71 (2H, d, J=7.2 Hz), 3.96 (2H, br s), 5.14 (2H, d,J=12.5 Hz), 5.84 (1H, s), 7.35-7.46 (5H, m), 8.80 (2H, s).

Obs MS [M+1]: 274.5

Example 2551-{5-[(2,5-Difluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.79 (7H, d, J=6.6 Hz), 1.96-2.09 (1H, m),2.52 (3H, br t, J=5.3 Hz), 3.69 (2H, d, J=7.3 Hz), 3.97 (2H, br t, J=5.5Hz), 5.19 (2H, s), 5.94 (1H, s), 7.26-7.39 (2H, m), 7.40-7.47 (1H, m),8.95 (2H, s).

Obs MS [M+1]: 310.4

Example 2561-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.79 (6H, d, J=6.6 Hz), 1.97-2.08 (1H, m),2.54 (3H, br t, J=5.1 Hz), 3.69 (2H, d, J=7.2 Hz), 3.98 (2H, br t, J=5.0Hz), 5.20 (2H, s), 5.91 (1H, s), 7.35 (1H, t, J=9.4 Hz), 7.49-7.56 (1H,m), 7.65 (1H, dd, J=6.4, 2.9 Hz), 8.83 (2H, br s).

Obs MS [M+1]: 326.4

Example 2571-[5-(Benzyloxy)-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.89 (9H, s), 2.52 (3H, br t, J=5.0 Hz),3.68 (2H, br s), 3.96 (2H, br t, J=4.7 Hz), 5.14 (2H, s), 5.90 (1H, s),7.32-7.48 (5H, m), 8.99 (2H, br s).

Obs MS [M+1]: 288.3

Example 2581-{5-[(2,5-Difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-dG) δ: 0.86 (9H, s), 2.52 (3H, br t, J=5.1 Hz),3.67 (2H, s), 3.96 (2H, br t, J=5.1 Hz), 5.17 (2H, s), 5.98 (1H, s),7.26-7.39 (2H, m), 7.41-7.47 (1H, m), 9.07 (2H, br s).

Obs MS [M+1]: 324.4

Example 2591-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.86 (9H, s), 2.52 (3H, br d, J=5.1 Hz),3.66 (2H, s), 3.96 (2H, br t, J=5.3 Hz), 5.18 (2H, s), 5.98 (1H, s),7.35 (1H, t, J=9.2 Hz), 7.49-7.55 (1H, m), 7.66 (1H, dd, J=6.1, 2.6 Hz),9.06 (2H, br s).

Obs MS [M+1]: 340.4

Example 2601-[5-(Benzyloxy)-1-(2-ethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.81 (6H, t, J=7.4 Hz), 1.14-1.28 (4H, m),1.65-1.79 (1H, m), 2.53 (3H, br s), 3.79 (2H, br d, J=6.8 Hz), 3.97 (2H,br t, J=5.8 Hz), 5.16 (2H, s), 5.87 (1H, s), 7.36-7.47 (5H, m), 8.87(2H, br s).

Obs MS [M+1]: 302.5

Example 2611-{5-[(3-Chlorobenzyl)oxy]-1-(2-ethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Obs MS [M+1]: 336.4

Example 2621-{5-[(2,5-Difluorobenzyl)oxy]-1-(2-ethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Obs MS [M+1]: 338.4

Example 2631-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(2-ethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Obs MS [M+1]: 354.4

Example 2641-[5-(Benzyloxy)-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.88 (9H, s), 1.53-1.58 (2H, m), 2.52 (3H,br s), 3.88-3.98 (4H, m), 5.18 (2H, s), 5.89 (1H, s), 7.37-7.48 (5H, m),8.94 (2H, br s).

Obs MS [M+1]: 302.5

Example 2651-{5-[(3-Chlorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90 (9H, s), 1.53-1.59 (2H, m), 2.52 (3H,br s), 3.90-3.97 (4H, m), 5.20 (2H, s), 5.90 (1H, br s), 7.40-7.47 (3H,m), 7.53 (1H, br s), 9.04 (2H, br s).

Obs MS [M+1]: 336.4

Example 2661-{5-[(2,5-Difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.87 (9H, s), 1.51-1.56 (2H, m), 2.52 (3H,br s), 3.86-3.92 (2H, m), 3.96 (2H, br t, J=5.1 Hz), 5.22 (2H, s), 5.96(1H, br s), 7.27-7.39 (2H, m), 7.40-7.47 (1H, m), 9.01 (2H, br s).

Obs MS [M+1]: 338.4

Example 2671-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.87 (9H, s), 1.51-1.56 (2H, m), 2.53 (3H,t, J=4.5 Hz), 3.87-3.92 (2H, m), 3.97 (2H, br t, J=5.7 Hz), 5.23 (2H,s), 5.95 (1H, s), 7.37 (1H, t, J=9.3 Hz), 7.50-7.56 (1H, m), 7.66 (1H,dd, J=6.3, 2.7 Hz), 8.95 (2H, br s).

Obs MS [M+1]: 354.3

Example 2681-[5-(Benzyloxy)-1-(3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.90 (6H, d, J=6.4 Hz), 1.44-1.57 (1H, m),1.59-1.65 (2H, m), 2.61 (3H, br s), 3.95 (2H, t, J=7.3 Hz), 4.09 (2H, brs), 5.09 (2H, s), 6.11 (1H, s), 7.34-7.41 (5H, m), 9.78 (2H, br s).

Obs MS [M+1]: 288.3

Example 2691-{5-[(2,5-Difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.45-1.68 (3H, m),2.63 (3H, br s), 3.96 (2H, br t, J=7.3 Hz), 4.10 (2H, br s), 5.13 (2H,s), 6.15 (1H, s), 7.02-7.10 (2H, m), 7.12-7.18 (1H, m), 9.80 (2H, s).

Obs MS [M+1]: 324.4

Example 2701-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.91 (6H, d, J=6.4 Hz), 1.47-1.67 (3H, m),2.63 (3H, br s), 3.95 (2H, br t, J=7.2 Hz), 4.10 (2H, br s), 5.11 (2H,s), 6.11 (1H, d, J=7.0 Hz), 7.03-7.09 (1H, m), 7.28-7.35 (1H, m), 7.42(1H, dd, J=6.2, 2.4 Hz), 9.77 (2H, d, J=0.9 Hz).

Obs MS [M+1]: 340.4

Example 2711-[5-(Benzyloxy)-1-(4,4,4-trifluorobutyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 2.04 (4H, m), 2.62 (3H, s), 4.01 (2H, m),4.09 (2H, br s), 5.10 (2H, s), 6.15 (1H, s), 7.39 (5H, m), 9.81 (2H, brs).

Obs MS [M+1]: 328.3

Example 2721-{5-[(2,5-Difluorobenzyl)oxy]-1-(4,4,4-trifluorobutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 2.04 (4H, m), 2.62 (3H, s), 4.01 (2H, m),4.09 (2H, br s), 5.13 (2H, s), 6.18 (1H, br s), 7.03-7.09 (2H, m), 7.14(1H, m), 9.86 (2H, br s)

Obs MS [M+1]: 364.2

Example 2731-[5-(Benzyloxy)-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.08 (6H, s), 1.76-1.83 (2H, m), 2.52 (3H,br t, J=5.5 Hz), 3.05 (3H, s), 3.88-3.97 (4H, m), 5.16 (2H, s), 5.87(1H, s), 7.35-7.47 (5H, m), 8.93 (2H, br s).

Obs MS [M+1]: 318.2

Example 2741-{5-[(2,5-Difluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.07 (6H, s), 1.75-1.83 (2H, m), 2.53 (3H,br t, J=4.4 Hz), 3.04 (3H, s), 3.87-3.99 (4H, m), 5.21 (2H, s), 5.93(1H, s), 7.29-7.38 (2H, m), 7.44 (1H, dd, J=8.7, 5.6 Hz), 8.94 (2H, s).

Obs MS [M+1]: 354.4

Example 2751-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.08 (6H, s), 1.75-1.82 (2H, m), 2.53 (3H,br t, J=5.1 Hz), 3.04 (3H, s), 3.86-3.99 (4H, m), 5.21 (2H, s), 5.93(1H, s), 7.35 (1H, t, J=9.3 Hz), 7.49-7.56 (1H, m), 7.66 (1H, dd, J=6.3,2.7 Hz), 8.94 (2H, s).

Obs MS [M+1]: 370.3

Examples 276 to 282

The compounds of Examples 276 to 282 as shown in Table 12 were preparedin the same manner as in Examples 20 to 40 except that the compoundobtained in Reference Example 1 and a corresponding benzyl chloride orbenzyl bromide were used. Step (i) was carried out by Method C describedas a general process in Examples 20 to 40.

TABLE 12

Ex. X Y Z Obs MS [M + 1] 276□ 2-F 3-F 4-F 354.4 277□ 2-F 3-F 5-F 354.4278□ 2-F 3-F 6-F 354.4 279□ 2-F 3-Me 6-F 350.4 280□ 2-F 4-F 5-F 354.4281□ 2-F 4-F 6-F 354.4 282□ 2-Cl 4-F 5-F 370.3

Example 2761-{1-(Cyclopentylmethyl)-5-[(2,3,4-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (2H, m), 1.60-1.75 (6H, m), 2.41 (1H,m), 2.69 (3H, s), 3.95 (2H, d, J=8.0 Hz), 4.24 (2H, s), 5.22 (2H, s),6.60 (1H, s), 7.05 (1H, m), 7.25 (1H, m), 10.14 (2H, br s).

Example 2771-{1-(Cyclopentylmethyl)-5-[(2,3,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.20 (2H, m), 1.45-1.70 (6H, m), 2.36 (1H,m), 2.61 (3H, s), 3.86 (2H, d, J=8.0 Hz), 4.11 (2H, s), 5.15 (2H, s),6.22 (1H, s), 6.90-7.00 (2H, m), 9.82 (2H, br s).

Example 2781-{1-(Cyclopentylmethyl)-5-[(2,3,6-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.16 (2H, m), 1.44-1.65 (6H, m), 2.31 (1H,m), 2.60 (3H, s), 3.78 (2H, d, J=8.0 Hz), 4.09 (2H, s), 5.16 (2H, s),6.19 (1H, s), 6.89 (1H, m), 7.18 (1H, m), 9.78 (2H, br s).

Example 2791-{1-(Cyclopentylmethyl)-5-[(2,6-difluoro-3-methylbenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.16 (2H, m), 1.40-1.65 (6H, m), 2.23 (3H,s), 2.31 (1H, m), 2.61 (3H, s), 3.78 (2H, d, J=8.0 Hz), 4.10 (2H, s),5.14 (2H, s), 6.20 (1H, s), 6.79-6.85 (1H, m), 7.13-7.22 (1H, m), 9.82(2H, br s).

Example 2801-{1-(Cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.19 (2H, m), 1.50-1.70 (6H, m), 2.38 (1H,m), 2.63 (3H, s), 3.88 (2H, d, J=8.0 Hz), 4.15 (2H, s), 5.11 (2H, s),6.35 (1H, s), 6.94-7.02 (1H, m), 7.24-7.32 (1H, m), 9.97 (2H, br s).

Example 2811-{1-(Cyclopentylmethyl)-5-[(2,4,6-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.16 (2H, m), 1.45-1.70 (6H, m), 2.30 (1H,m), 2.60 (3H, s), 3.77 (2H, d, J=8.0 Hz), 4.08 (2H, s), 5.09 (2H, s),6.15 (1H, s), 6.71 (2H, dd, J=8.0, 8.0 Hz), 9.76 (2H, br s).

Example 2821-{5-[(2-Chloro-4,5-difluorobenzyl)oxy]-1-(cyclopentyl-methyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (400 MHz, CDCl₃) δ: 1.20 (2H, m), 1.45-1.70 (6H, m), 2.32 (1H,m), 2.63 (3H, s), 3.88 (2H, d, J=8.0 Hz), 4.12 (2H, s), 5.12 (2H, s),6.24 (1H, s), 7.24-7.38 (2H, m), 9.89 (2H, br s).

Example 283N-Methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

The title compound was prepared in the same manner as in Example 280except that the compound in Reference Example 24 was used.

¹H-NMR (400 MHz, CDCl₃) δ: 0.88 (6H, d, J=6.0 Hz), 1.40-1.70 (5H, m),2.59 (3H, s), 3.91 (2H, d, J=6.0 Hz), 4.06 (2H, s), 5.06 (2H, s), 6.11(1H, s), 6.93-7.01 (1H, m), 7.22-7.35 (1H, m).

Example 2841-{1-(3,3-Dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

The title compound was prepared in the same manner as in Example 280except that the compound obtained in Reference Example 22 was used.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (9H, s), 1.60-1.65 (2H, m), 2.59 (3H,s), 3.89-3.94 (2H, m), 4.07 (2H, s), 5.07 (2H, s), 6.13 (1H, s),6.93-7.02 (1H, m), 7.25-7.35 (1H, m), 9.77 (2H, br s).

Example 2851-{1-(4-Methoxybenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

The title compound was prepared in the same manner as in Example 198.

¹H-NMR (400 MHz, CDCl₃) δ: 2.58 (3H, s), 3.76 (3H, s), 4.06 (2H, s),5.03 (2H, s), 5.03 (2H, s), 6.13 (1H, s), 6.80 (2H, d, J=8.0 Hz),6.90-6.96 (1H, m), 7.08 (2H, d, J=8.0 Hz), 7.23-7.29 (1H, m), 9.79 (2H,br s).

Example 286

N-Methyl-1-{1-(4-methylbenzyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

The title compound was prepared in the same manner as in Example 198.

¹H-NMR (400 MHz, CDCl₃) δ: 2.29 (3H, s), 2.58 (3H, s), 4.06 (2H, s),5.03 (2H, s), 5.05 (2H, s), 6.14 (1H, s), 6.88-6.96 (1H, m), 7.01 (2H,d, J=8.0 Hz), 7.08 (2H, d, J=8.0 Hz), 7.21-7.26 (1H, m), 9.80 (2H, brs).

Example 2872-({3-[(Methylamino)methyl]-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-1-yl}methyl)benzonitrilehydrochloride

The title compound was prepared in the same manner as in Example 198.

¹H-NMR (400 MHz, CDCl₃) δ: 2.61 (3H, s), 4.07 (2H, s), 5.07 (2H, s),5.32 (2H, s), 6.19 (1H, s), 6.88-6.96 (1H, m), 7.06-7.16 (2H, m), 7.38(1H, dd, J=8.0, 8.0 Hz), 7.52 (1H, dd, J=8.0, 8.0 Hz), 7.64 (1H, d,J=8.0 Hz), 9.85 (2H, br s).

Example 2881-[5-(Benzyloxy)-1-(1-cyclopentylethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

Step (i)

To a solution of Compound (Ir) obtained in Reference Example 6 (40 mg,0.12 mmol) and cesium carbonate (81 mg, 0.25 mmol) in acetonitrile (0.6mL) was added a corresponding benzyl chloride (21 μL, 0.19 mmol) at roomtemperature, and the reaction mixture was stirred at room temperaturefor 3 hours. The salt was filtered off, the filtrate was concentrated,and the concentrated residue was purified by PTLC (n-hexane:ethylacetate=70:30) to give Compound (IIr) (33 mg, 64%)

Step (ii)

The Compound (IIr) was dissolved in chloroform (0.6 mL), to the solutionwas added 4 mol/L HCl/1,4-dioxane (0.6 mL) at room temperature, thereaction mixture was stirred at room temperature for 30 minutes, and thesolvent was evaporated under reduced pressure. The residue was purifiedby adding diethyl ether and removing the supernatant by decantation, andthe resultant solid was dried under reduced pressure to give the titleCompound (IIIr) (26 mg, 95%) as a light brown powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90-1.03 (1H, m), 1.14-1.27 (2H, m), 1.31(3H, d, J=6.6 Hz), 1.34-1.63 (4H, m), 1.67-1.80 (1H, m), 2.16-2.30 (1H,m), 2.50 (3H, br s), 3.95 (2H, br, J=5.6 Hz), 3.99-4.08 (1H, m), 5.14(2H, s), 5.86 (1H, s), 7.32-7.46 (5H, m), 8.92 (2H, br s).

Examples 289 to 291

The compounds of Examples 289 to 291 were prepared in the same manner asin Example 288 except that the ketone compound obtained in ReferenceExample 6 and a corresponding benzyl chloride were used.

Example 2891-{5-[(3-Chlorobenzyl)oxy]-1-(1-cyclopentylethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90-1.02 (1H, m), 1.17-1.27 (2H, m), 1.32(3H, d, J=6.8 Hz), 1.35-1.65 (4H, m), 1.69-1.80 (1H, m), 2.16-2.30 (1H,m), 2.50 (3H, br s), 3.94 (2H, br t, J=5.6 Hz), 3.99-4.09 (1H, m), 5.17(2H, s), 5.87 (1H, s), 7.39-7.47 (3H, m), 7.50 (1H, br s), 9.03 (2H, brs).

Example 2901-{1-(1-Cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.87-0.99 (1H, m), 1.12-1.27 (2H, m), 1.30(3H, d, J=6.6 Hz), 1.34-1.60 (4H, m), 1.66-1.80 (1H, m), 2.21 (1H, brdt, J=25.6, 8.2 Hz), 2.50 (3H, br s), 3.94-4.05 (3H, m), 5.18 (2H, s),5.93 (1H, s), 7.25-7.38 (2H, m), 7.40-7.46 (1H, m), 8.98 (2H, br s).

Example 2911-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(1-cyclopentylethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.86-0.98 (1H, m), 1.12-1.26 (2H, m), 1.29(3H, d, J=6.6 Hz), 1.33-1.60 (4H, m), 1.65-1.77 (1H, m), 2.20 (1H, brtd, J=17.1, 8.9 Hz), 2.50 (3H, br s), 3.91-4.03 (3H, m), 5.18 (2H, s),5.93 (1H, s), 7.34 (1H, t, J=9.2 Hz), 7.51 (1H, ddd, J=8.8, 4.4, 2.8Hz), 7.63 (1H, br dd, J=6.2, 2.8 Hz), 8.99 (2H, br s).

Examples 292 to 295

The compounds of Examples 292 to 295 were prepared in the same manner asin Example 288 except that the compound obtained in Reference Example 7and a corresponding benzyl chloride or benzyl bromide were used.

Example 2921-[5-(Benzyloxy)-1-(1-cyclohexylethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.71-1.23 (6H, m), 1.30 (3H, d, J=6.8 Hz),1.55-1.80 (5H, m), 2.51 (3H, br s), 3.93-4.04 (2H, m), 4.12-4.25 (1H,m), 5.15 (2H, br s), 5.84-5.93 (1H, m), 7.34-7.46 (5H, m), 8.83-9.13(2H, m).

Obs MS [M+1]: 328.3

Example 2931-{1-(1-Cyclohexylethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.74-1.00 (2H, m), 1.03-1.28 (4H, m), 1.39(3H, d, J=7.0 Hz), 1.61-1.88 (5H, m), 2.45 (3H, s), 3.65 (2H, s),3.91-4.02 (1H, m), 5.12 (2H, s), 5.56 (1H, s), 7.06-7.13 (1H, m), 7.17(1H, ddd, J=7.5, 7.5, 1.1 Hz), 7.31-7.39 (1H, m), 7.43 (1H, ddd, J=7.5,7.5, 1.8 Hz)

Obs MS [M+1]: 346.5

Example 2941-{1-(1-Cyclohexylethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.73-1.32 (6H, m), 1.40 (3H, d, J=6.6 Hz),1.56-1.90 (5H, m), 2.61 (3H, s), 3.97-4.23 (3H, m), 5.09 (2H, s), 6.13(1H, s), 7.01-7.21 (3H, m), 7.31-7.42 (1H, m), 9.75 (2H, br s).

Obs MS [M+1]: 346.2

Example 2951-{1-(1-Cyclohexylethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.69-1.35 (6H, m), 1.43 (3H, d, J=5.3 Hz),1.53-1.89 (5H, m), 2.65 (3H, s), 3.98-4.35 (3H, m), 5.12 (2H, s), 6.34(1H, s), 7.03-7.17 (2H, m), 7.31-7.50 (2H, m), 9.92 (2H, br s).

Obs MS [M+1]: 346.2

Examples 296 to 308

The compounds of Examples 296 to 308 as shown in Table 13 were preparedin the same manner as in Examples 20 to 40 except that the compoundobtained in Reference Example 7 and a corresponding benzyl bromide orbenzyl chloride were used.

TABLE 13 Benzylation Obs MS Ex. X Y method Salt [M + 1] 296□ 2-Cl H CFree base 362.2 297□ 3-Cl H C Hydrochloride 362.5 298□ 2-Me H C Freebase 342.3 299□ 3-Me H B Hydrochloride 342.3 300□ 2-F 4-F BHydrochloride 364.5 301□ 2-Cl 4-F B Hydrochloride 380.2 302□ 2-Me 4-F BHydrochloride 360.5 303□ 2-F 5-F C Free base 364.2 304□ 2-F 5-Cl C Freebase 380.4 305□ 2-F 5-Me C Free base 360.2 306□ 2-Cl 5-F C Free base380.2 307□ 2-Me 5-F C Free base 360.5 308□ 3-Me 5-Me B Hydrochloride356.2

Examples 309 and 310

The compounds of Examples 309 and 310 were prepared in the same manneras in Example 288.

Example 3091-[5-(Benzyloxy)-1-(l-cyclohexylpropyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.64 (3H, t, J=7.3 Hz), 0.74-1.00 (2H, m),1.04-1.31 (4H, m), 1.62 (2H, m), 1.68-1.93 (5H, m), 2.62 (3H, s), 3.84(1H, dt, J=7.8, 7.8 Hz), 4.16 (2H, s), 5.12 (2H, s), 6.23 (1H, s), 7.40(5H, m), 9.90 (2H, br s).

Obs MS [M+1]: 342.3

Example 3101-{1-(1-Cyclohexylpropyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.63 (3H, t, J=7.2 Hz), 0.73-1.00 (2H, m),1.04-1.32 (4H, m), 1.56-1.91 (7H, m), 2.59 (3H, s), 3.77 (1H, dt, J=8.0,8.0 Hz), 4.12 (2H, s), 5.12 (2H, s), 6.14 (1H, s), 7.05 (2H, m), 7.14(1H, m), 9.80 (2H, br s).

Obs MS [M+1]: 378.5

Examples 311 to 327

The compounds of Examples 311 to 327 as shown in Table 14 were preparedin the same manner as in Examples 20 to 40 except that the compoundsobtained in Reference Examples 31 to 35 and a corresponding benzylchloride or benzyl bromide were used. The benzylation in Step (i) wascarried out by Method C described as a general process in Examples 20 to40.

TABLE 14

Obs MS Ex. R X Y Salt [M + 1] 311□

2-F 5-F Hydrochloride 350.4 312□

H H Hydrochloride 328.6 313□

2-F 5-F Hydrochloride 364.2 314□

2-F 5-Cl Hydrochloride 380.4 315□

2-F 5-F Hydrochloride 364.5 316□

H H Hydrochloride 342.3 317□

2-Cl H Free base 376.5 318□

3-Cl H Free base 376.5 319□

4-Cl H Free base 376.5 320□

2-F 3-F Free base 378.5 321□

2-F 4-F Free base 378.5 322□

2-F 5-F Hydrochloride 378.5 323□

2-F 6-F Free base 378.5 324□

3-F 4-F Free base 378.5 325□

3-F 5-F Free base 378.5 326□

H H Hydrochloride 316.6 327□

2-F 5-F Hydrochloride 352.4 (*shows the bonding position)

Example 3282-{5-(Benzyloxy)-3-[(methylamino)methyl]-H-pyrazol-1-yl}-2-cyclohexyl-ethanolhydrochloride

Step (i)

To a solution of Compound (Is) prepared in Reference Example 42 (238 mg,1.0 mmol) and triethylamine (147 μL, 1.1 mmol) in ethanol (8 mL) wasadded the Compound (IIa) prepared in Step (i) of Reference Example 1(262 mg, 1.0 mmol) at room temperature, and the reaction mixture wasstirred at 80° C. for 16 hours. To the resultant was added triethylamine(147 μL, 1.1 mmol), and the reaction mixture was stirred at 80° C. for3.5 hours. The mixture was cooled to room temperature, poured into 5%aq. KHSO₄ (20 mL), and extracted with ethyl acetate. The organic layerwas dried, the solvent was evaporated under reduced pressure, and theconcentrated residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=50:50) to give Compound (IIs) (189 mg, 47%) as abrown oil.

Step (ii)

To a solution of the Compound (IIs) (50 mg, 0.13 mmol) and cesiumcarbonate (82 mg, 0.25 mmol) in acetonitrile (0.65 mL) was added benzylchloride (22 μL, 0.19 mmol) at room temperature, and the reactionmixture was stirred at room temperature for 2.5 hours. The resultant wasdiluted with ethyl acetate, the salt was filtered off, the filtrate wasconcentrated, and the concentrated residue was purified by PTLC(n-hexane:ethyl acetate=7:3) to give Compound (IIIs) (26 mg, 42%).

Step (iii)

To a solution of the Compound (IIIs) (26 mg, 0.054 mmol) intetrahydrofuran (0.3 mL) was added lithium aluminum hydride (7 mg, 0.18mmol) at 0° C., and the reaction mixture was stirred for 10 minutes. Tothe mixture was further added lithium aluminum hydride (12 mg, 0.32mmol) at 0° C., and the reaction mixture was stirred for 10 minutes. Tothe mixture was added lithium aluminum hydride (10 mg, 0.31 mmol) at 0°C., and the reaction mixture was stirred for 40 minutes. To the mixturewas added sat. aq. Na₂SO₄, the mixture was filtered, the filtrate wasconcentrated, and the concentrated residue was purified by silica gelcolumn chromatography (ethyl acetate) to give Compound (IVs) (29 mg,quantitative)

Step (iv)

To a solution of the Compound (IVs) (29 mg, mmol) in chloroform (0.5 mL)was added 4 mol/L HCl/1,4-dioxane (0.5 mL) at room temperature, and thereaction solution was stirred at room temperature for 1 hour. Thesolvent was evaporated under reduced pressure to give the title Compound(Vs) (8.3 mg, 40%) as a brown oil.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.71-1.83 (11H, m), 2.53 (3H, br s), 3.76(2H, m), 3.92-4.01 (3H, m), 4.58 (1H, br s), 5.14 (2H, s), 5.79 (1H, s),7.35-7.45 (5H, m), 8.73 (2H, br s).

Example 3292-Cyclohexyl-2-{5-[(2,5-difluorobenzyl)oxy]-3-[(methyl-amino)methyl]-1H-pyrazol-1-yl}ethanolhydrochloride

The title compound was prepared in the same manner as in Example 328.

¹H-NMR (300 MHz, CDCl₃) δ: 0.76-1.33 (6H, m), 1.55-1.99 (5H, m), 2.65(3H, s), 3.82 (1H, m), 3.95-4.17 (4H, m), 5.12 (2H, s), 6.05 (1H, s),7.05 (2H, m), 7.14 (1H, m), 9.57 (1H, br s), 9.81 (1H, br s).

Example 3301-[5-(Benzyloxy)-1-(1-cyclohexyl-2-fluoroethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (IVs) prepared in Step (iii) of Example328 (40 mg, 0.090 mmol) in tetrahydrofuran (1 mL) was addedperfluorobutane sulfonyl fluoride (32 μL, 0.18 mmol) at 0° C. To themixture was added DBU (27 μL, 0.18 mmol) at 0° C., and the reactionmixture was stirred for 80 minutes at 0° C. and then for 3 hours withslowly warming to room temperature. To the mixture was added sat. aq.NaHCO₃, the mixture was extracted with ethyl acetate, the organic layerwas washed with 5% KHSO₄, and the solvent was evaporated under reducedpressure. The concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=4:1) to give Compound (It) (31mg, 59%) as an oil.

Step (ii)

To a solution of the Compound (It) (31 mg, 0.070 mmol) in chloroform(0.4 mL) was added 4 mol/L HCl/1,4-dioxane (0.5 mL) at room temperature,and the reaction solution was stirred at room temperature for 1 hour.The solvent was evaporated under reduced pressure, the concentratedresidue was purified by adding diethyl ether and removing thesupernatant by decantation to give the title Compound (IIt) (24 mg, 90%)as a white powder.

¹H-NMR (300 MHz, CDCl₃) δ: 0.89 (1H, m), 0.96-1.33 (5H, m), 1.57-1.96(5H, m), 2.59 (3H, s), 4.10 (2H, s), 4.27 (1H, m), 4.71 (1H, ddd,J=45.8, 9.7, 4.0 Hz), 4.82 (1H, ddd, J=48.2, 8.9, 8.9 Hz), 5.09 (2H, s),6.10 (1H, s), 7.39 (5H, m), 9.77 (2H, br s).

Examples 331 to 339

The compounds of Examples 331 to 339 as shown in Table 15 were preparedin the same manner as in Examples 20 to 40 except that the compoundsobtained in Reference Examples 27 to 30 and a corresponding benzylbromide or benzyl chloride were used.

TABLE 15

Benzylation Obs MS Ex. Z X Y method [M + 1] 331□ 1-Me H H B 328.6 332□1-Me 3′-Cl H B 362.5 333□ 1-Me 2′-F 5′-F C 364.5 334□ 2-Me H H B 328.3335□ 2-Me 3′-Cl H B 362.2 336□ 3-Me H H B 328.3 337□ 3-Me 3′-Cl H B362.5 338□ 4-Me H H B 328.6 339□ 4-Me 3′-Cl H B 362.5

Example 3401-[5-(Benzyloxy)-1-(3,4-dihydro-2H-chromen-2-ylmethyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

Step (i)

Compound (IIu) was prepared in the same manner as in Reference Example42 except that Chroman-2-ylmethyl alcohol (Iu) was used.

Steps (ii) to (iv)

The desired Compound (Vu) was prepared in the same manner as in Steps(ii) to (iv) of Example 198.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.62-1.73 (1H, m), 1.94-2.02 (1H, m), 2.54(3H, br t, J=5.2 Hz), 2.66-2.83 (2H, m), 3.99 (2H, br t, J=5.6 Hz), 4.13(1H, dd, J=14.1, 5.1 Hz), 4.25 (1H, dd, J=14.3, 6.7 Hz), 4.32-4.39 (1H,m), 5.20 (2H, s), 5.91 (1H, s), 6.65 (1H, br d, J=8.0 Hz), 6.81 (1H, brt, J=7.0 Hz), 7.05 (2H, br t, J=7.6 Hz), 7.33-7.48 (5H, m), 8.96 (2H, brs).

Example 3411-{5-[(3-Chlorobenzyl)oxy]-1-(3,4-dihydro-2H-chromen-2-yl-methyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

The title compound was prepared in the same manner as in Example 340.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.64-1.74 (1H, m), 1.96-2.03 (1H, m), 2.54(3H, br t, J=4.3 Hz), 2.69-2.84 (2H, m), 3.98 (2H, br t, J=5.2 Hz), 4.16(1H, dd, J=14.0, 5.0 Hz), 4.26 (1H, dd, J=14.4, 6.8 Hz), 4.33-4.40 (1H,m), 5.21 (2H, s), 5.90-5.96 (1H, m), 6.65 (1H, br d, J=8.0 Hz), 6.81(1H, br t, J=7.4 Hz), 7.01-7.08 (2H, m), 7.41-7.47 (3H, m), 7.54 (1H,s), 9.01 (2H, br s).

Example 342N-({1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)cyclopropanamine

The title compound (39 mg, 52%) was prepared in the same manner as inSteps (i) to (iv) of Reference Example 36 except that lithiumborohydride was used instead of lithium aluminum hydride in Step (iii)of Reference Example 36.

¹H-NMR (300 MHz, CDCl₃) δ: 0.35-0.46 (4H, m), 0.87-1.04 (2H, m),1.09-1.30 (3H, m), 1.54-1.94 (6H, m), 2.15-2.25 (1H, m), 3.73-3.79 (4H,m), 5.09 (2H, s), 5.53 (1H, s), 6.97-7.18 (3H, m).

The compounds in the following Examples 343 to 346 were prepared in thesame manner as in Example 342.

Example 3431-{1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N,N-dimethylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.87-1.04 (2H, m), 1.09-1.30 (3H, m),1.50-1.97 (6H, m), 2.27 (6H, s), 3.37 (2H, s), 3.77 (2H, d, J=7.2 Hz),5.10 (2H, s), 5.59 (1H, s), 6.97-7.18 (3H, m).

Example 344N-({1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)ethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.86-1.02 (2H, m), 1.07-1.29 (6H, m),1.44-1.94 (6H, m), 2.70 (2H, q, J=7.2 Hz), 3.69 (2H, s), 3.75 (2H, d,J=7.3 Hz), 5.10 (2H, s), 5.56 (1H, s), 6.97-7.18 (3H, m).

Example 345N-({1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)propan-1-amine

¹H-NMR (300 MHz, CDCl₃) δ: 0.84-1.03 (5H, m), 1.08-1.30 (3H, m),1.43-1.93 (8H, m), 2.61 (2H, q, J=7.3 Hz), 3.69 (2H, s), 3.75 (2H, d,J=7.2 Hz), 5.10 (2H, s), 5.55 (1H, s), 6.96-7.18 (3H, m).

Example 346N-({1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methyl)propan-2-amine

¹H-NMR (300 MHz, CDCl₃) δ: 0.85-1.03 (2H, m), 1.09 (6H, d, J=6.2 Hz),1.13-1.28 (3H, m), 1.48-1.93 (6H, m), 2.81-2.91 (1H, m), 3.68 (2H, s),3.75 (2H, d, J=7.3 Hz), 5.09 (2H, s), 5.55 (1H, s), 6.97-7.18 (3H, m).

Example 3471-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

Steps (i) to (iii)

To a solution of Compound (Iw) prepared in the same manner as in Steps(i) to (iii) of Example 1 (190 mg, 0.59 mmol) and triethylamine (164 μL,1.2 mmol) in dichloromethane (3 mL) was added methanesulfonyl chloride(68 μL, 0.88 mmol) at 0° C., and the reaction mixture was stirred at 0°C. for 25 minutes. To the mixture was further added methanesulfonylchloride (9 μL, 0.12 mmol), and the mixture was stirred at 0° C. for 5minutes. To the reaction mixture was added sat. aq. NaHCO₃, and themixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous Na₂SO₄, and the solvent was evaporated underreduced pressure to give a concentrated residue, which was used in thenext step without further purification. The residue was dissolved in DMF(1.2 mL), sodium azide (77 mg, 1.2 mmol) was added to the solution atroom temperature, and the reaction mixture was stirred at roomtemperature for 1.5 hours. To the reaction solution was added water (5mL), the mixture was extracted with toluene, the combined organic layerswere washed with water, and the solvent was evaporated under reducedpressure to give a crude product of Compound (IIw) (186 mg).

The Compound (IIw) was dissolved in tetrahydrofuran (3 mL), to thesolution were added triphenylphosphine (186 mg, 0.71 mmol) and water(0.6 mL) at room temperature, and the reaction mixture was stirred atroom temperature overnight. The solvent was evaporated under reducedpressure, the concentrated residue was purified by silica gel columnchromatography (chloroform:methanol=99:1--->10:1) to give a free base ofCompound (IIIw) (61 mg). The product was dissolved in chloroform (0.4mL), and 4 mol/L HCl/1,4-dioxane (0.4 mL) was added to the solution. Thesolvent was evaporated under reduced pressure, and to the concentratedresidue was added diethyl ether. The resulting precipitate was collectedby filtration, washed with diethyl ether (10 mL), and dried underreduced pressure to give the title Compound (IIIw) (70 mg, 33%) as alight brown solid.

¹H-NMR (300 MHz, CDCl₃) δ: 1.21 (2H, m), 1.45-1.77 (6H, m), 2.50 (1H,m), 4.10 (2H, d, J=8.1 Hz), 4.60 (2H, br s), 5.40 (2H, s), 6.97 (1H, s),7.07 (2H, m), 7.26 (1H, m), 9.16 (3H, br s).

Obs MS [M+1]: 322.4

Example 3481-{5-[(2,5-Difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}methanaminehydrochloride

The title compound was prepared in the same manner as in Example 347.

¹H-NMR (300 MHz, CDCl₃) δ: 0.88 (6H, d, J=6.6 Hz), 1.50 (1H, m), 1.67(2H, m), 4.07 (2H, m), 4.43 (2H, s), 5.27 (2H, s), 6.59 (1H, s), 7.06(2H, m), 7.26 (1H, m), 8.98 (3H, s).

Obs MS [M+1]: 310.4

Example 3491-{1-(Cyclohexylmethyl)-5-[difluoro(phenyl)methoxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of Compound (Ix) prepared in Reference Example 4 (100 mg,0.31 mmol) and cesium carbonate (151 mg, 0.46 mmol) in acetonitrile (2mL) was added a solution of Compound (IIx) prepared according to themethod disclosed in Synthetic Communications. 1999, 855-862. (96 mg,0.46 mmol) in acetonitrile (1 mL), and the reaction solution was stirredat 50° C. for 1 day. The mixture was cooled to room temperature anddiluted with ethyl acetate. The salt was filtered off, the filtrate wasconcentrated, and the concentrated residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=94:6--->73:27) to giveCompound (IIIx) (49 mg, 36%) as a yellow oil.

Step (ii)

To a solution of Compound (IIIx) (47 mg, 0.11 mmol) in chloroform (1 mL)was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature, and thereaction solution was stirred for 30 minutes. The solution wasconcentrated under reduced pressure to give the title Compound (IVx) (43mg, quantitative) as a yellow oil.

¹H-NMR (300 MHz, CD₃OD) δ: 0.90-1.07 (2H, m), 1.13-1.27 (3H, m),1.51-1.77 (5H, m), 1.81-1.96 (1H, m), 2.72 (3H, s), 3.88 (2H, d, J=7.2Hz), 4.13 (2H, s), 6.19 (1H, t, J=1.8 Hz), 7.51-7.66 (3H, m), 7.68-7.76(2H, m).

Obs MS [M+1]: 350.4

Example 3501-{5-[1-(3-Chlorophenyl)ethoxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

The title compound (55 mg, 45%) as a pale-yellow oil was prepared in thesame manner as in the general processes of Examples 20 to 40 by usingthe compound prepared in Reference Example 4. The benzylation step wascarried out by Method B described as a general process in Examples 20 to40.

¹H-NMR (300 MHz, CD₃OD) δ: 0.93-1.10 (2H, m), 1.15-1.31 (3H, m),1.49-1.93 (6H, m), 1.66 (3H, d, J=6.4 Hz), 2.63 (3H, s), 3.84 (2H, dd,J=7.3, 3.1 Hz), 3.97 (2H, s), 5.32 (1H, q, J=6.5 Hz), 5.58 (1H, s),7.26-7.39 (3H, m), 7.40-7.43 (1H, m).

Obs MS [M+1]: 362.5

Example 3511-{1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-4-fluoro-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of Compound (Iy) prepared in Reference Example 4 (500 mg,1.6 mmol) and cesium carbonate (756 mg, 2.3 mmol) in acetonitrile (3 mL)was added a solution of 2,5-difluorobenzylbromide (377 mg, 2.3 mmol) inaceto-nitrile (2 mL) at room temperature, and the reaction mixture wasstirred at room temperature for 15 hours. To the solution was addedethyl acetate, the salt was filtered off, the filtrate was concentrated,and the concentrated residue was purified by silica gel columnchromatography (n-hexane--->n-hexane:ethyl acetate=80:20) to giveCompound (IIy) (518 mg, 74%) as a pale-yellow oil.

Step (ii)

To a solution of the Compound (IIy) (40 mg, 0.089 mmol) indimethylformamide (5 mL) was added a solution of Selectfluor (trademark)(38 mg, 0.11 mmol) in water (0.5 mL) with ice-cooling, and the reactionmixture was stirred for 1 hour at ice temperature and then stirredovernight with slowly warming to room temperature. To the mixture wasadded water (20 mL), the mixture was extracted with ethyl acetate, thecombined organic layers were dried over anhydrous MgSO₄, and the solventwas evaporated under reduced pressure. The concentrated residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=96:4--->75:25) to give Compound (IIIy) (19 mg, 44%) as acolorless oil.

Step (iii)

To a solution of the Compound (IIIy) (19 mg, 0.040 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction solution was stirred for 30 minutes. The solution wasconcentrated under reduced pressure to give the title compound (17 mg,quantitative) as a white solid.

¹H-NMR (300 MHz, CD₃OD) δ: 0.82-1.00 (2H, m), 1.07-1.25 (3H, m),1.44-1.55 (2H, m), 1.59-1.82 (4H, m), 2.72 (3H, s), 3.71 (2H, d, J=7.3Hz), 4.15 (2H, s), 5.36 (2H, s), 7.13-7.30 (3H, m).

Obs MS [M+l]: 368.4

Example 3521-{4-Chloro-1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (IIy) obtained in Step (i) of Example 351(40 mg, 0.089 mmol) in DMF (0.5 mL) was added N-chlorosuccinimide (14mg, 0.11 mmol) with ice-cooling, and the reaction mixture was stirredfor 1 hour at ice temperature and then stirred overnight with slowlywarming to room temperature. To the mixture was added water (20 mL), themixture was extracted with ethyl acetate, the combined organic layerswere dried over anhydrous MgSO₄, and the solvent was evaporated underreduced pressure. The concentrated residue was purified by silica gelcolumn chromatography (n-hexane--->n-hexane:ethyl acetate=83:17) to giveCompound (IIz) (33 mg, 76%) as a colorless oil.

Step (ii)

To a solution of Compound (IIz) (33 mg, 0.067 mmol) in chloroform (0.5mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature, andthe reaction solution was stirred for 30 minutes. The solution wasconcentrated under reduced pressure to give the title Compound (IIIz)(28 mg, quantitative) as a colorless oil.

¹H-NMR (300 MHz, CD₃OD) δ: 0.73-0.90 (2H, m), 0.99-1.16 (3H, m),1.36-1.47 (2H, m), 1.49-1.71 (4H, m), 2.66 (3H, s), 3.62 (2H, d, J=7.3Hz), 4.05 (2H, s), 5.31 (2H, s), 7.06-7.20 (3H, m).

Obs MS [M+1]: 384.3

Example 3531-{4-Bromo-1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (IIy) (400 mg, 0.89 mmol) in DMF (4 mL)was added N-bromosuccinimide (174 mg, 0.98 mmol) with ice-cooling, andthe reaction mixture was stirred overnight with slowly warming to roomtemperature. To the mixture was added water (40 mL), the mixture wasextracted with ethyl acetate, the combined organic layers were driedover anhydrous MgSO₄, and the solvent was evaporated under reducedpressure. The concentrated residue was purified by silica gel columnchromatography (n-hexane--->n-hexane:ethyl acetate=83:17) to giveCompound (IIaa) (333 mg, 71%) as a colorless oil.

Step (ii)

To a solution of the Compound (IIaa) (25 mg, 0.047 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction solution was stirred for 30 minutes. The solution wasconcentrated under reduced pressure to give the title Compound (IIIaa)(23 mg, quantitative) as a colorless oil.

¹H-NMR (300 MHz, CD₃OD) δ: 0.82-1.03 (2H, m), 1.09-1.26 (3H, m),1.45-1.57 (2H, m), 1.59-1.82 (4H, m), 2.75 (3H, s), 3.73 (2H, d, J=7.2Hz), 4.13 (2H, s), 5.39 (2H, d, J=1.1 Hz), 7.14-7.29 (3H, m).

Obs MS [M+1]: 428.3

Example 3541-{1-(Cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-4-methyl-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (IIaa) prepared in Step (i) of Example 353(50 mg, 0.095 mmol) and bis(tri-tert-butylphosphine)palladium (0) (9.7mg, 0.019 mmol) in tetra-hydrofuran (1 mL) was added methylzinc chloride(in 2.0 mol/L tetrahydrofuran, 62 μL, 0.12 mmol) at room temperature,and the reaction mixture was stirred at room temperature for 30 minutes.To the mixture were added water and sat. aq. NH₄Cl (10 mL), and themixture was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous MgSO₄, the solvent was evaporated underreduced pressure, and the concentrated residue was purified byreversed-phase liquid chromatography to give Compound (IIbb) (23 mg,51%) as a colorless oil. The conditions of the reversed-phasechromatography were the same as the conditions disclosed in Examples 20to 40.

Step (ii)

To a solution of the Compound (IIbb) (23 mg, 0.049 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction solution was stirred for 30 minutes. The solution wasconcentrated under reduced pressure to give the title Compound (IIIbb)(19 mg, 97%) as a white solid.

¹H-NMR (300 MHz, CD₃OD) δ: 0.82-1.01 (2H, m), 1.09-1.28 (3H, m),1.46-1.57 (2H, m), 1.60-1.83 (4H, m), 2.02 (3H, s), 2.71 (3H, s), 3.69(2H, d, J=7.3 Hz), 4.08 (2H, s), 5.17 (2H, d, J=1.1 Hz), 7.13-7.27 (3H,m).

Obs MS [M+1]: 364.5

Example 3551-[l-Benzyl-5-(benzylsulfanyl)-1H-pyrazol-3-yl]-N-methyl-methanaminehydrochloride

Steps (i) to (ii)

A solution of the Compound (VIIIb) prepared in Reference Example 36 (100mg, 0.32 mmol) and Lawesson's reagent [i.e.2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide](127 mg, 0.32 mmol) in toluene (2 mL) was stirred at 100° C. for 30minutes. To the solution were added benzyl bromide (56 μL, 0.47 mmol)and K₂CO₃ (131 mg, 0.95 mmol), and the reaction mixture was stirred at100° C. for 1 hour. The mixture was cooled to room temperature, the saltwas filtered off, the filtrate was concentrated, and the concentratedresidue was purified by silica gel column chromatography (n-hexane ethylacetate=4:1) to give Compound (IIIcc) (40 mg, 30%)

Step (iii)

To a solution of the Compound (IIIcc) (20 mg, 0.047 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction mixture was stirred for 30 minutes. The solvent wasevaporated under reduced pressure, the concentrated residue was purifiedby adding diethyl ether and removing the supernatant by decantation, andthe resulting solid was dried under reduced pressure to give the titleCompound (IVcc) (19 mg, quantitative) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆) δ: 9.13 (brs, 2H), 7.37-7.23 (m, 6H), 7.14(brd, 1H, J=6.4 Hz), 7.06 (brd, 2H, J=6.8 Hz), 6.59 (s, 1H), 5.24 (s,2H), 4.06 (s, 2H), 4.02 (s, 2H), 2.53-2.47 (s, 3H).

Example 3561-[5-(Benzylsulfanyl)-1-(3-phenylpropyl)-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

The title compound was prepared in the same manner as in Example 355.

¹H-NMR (400 MHz, CDCl₃) δ 9.87 (brs, 2H), 7.32-7.16 (m, 6H), 7.15-7.08(m, 4H), 6.78 (s, 1H), 4.14 (s, 2H), 3.91 (s, 2H), 3.85 (t, 2H, J=7.2Hz), 2.58 (s, 3H), 2.49 (t, 2H, J=7.2 Hz), 1.94 (tt, 2H, J=7.2, 7.2 Hz).

Example 357 N-Benzyl-1-(cyclohexylmethyl)-3-[(methyl]-1H-pyrazol-5-aminedihydrochloride

Step (i)

To a suspension of potassium tert-butoxide (9.90 g, 88 mmol) in THF (170mL) was added acetonitrile (3.62 g, 88 mmol) at 0° C., and the reactionsolution was stirred for 30 minutes with slowly warming to roomtemperature. The mixture was cooled to 0° C. again, a solution ofCompound (Idd) (13.8 g, 68 mmol) in tetrahydrofuran (50 mL) was addedthereto, and the reaction mixture was stirred for 2 hours with slowlywarming to room temperature. To the mixture was further added potassiumtert-butoxide (2.28 g, 26 mmol), and the reaction mixture was stirredfor 4 hours and then stirred at 50° C. for 30 minutes. The solution wascooled to 0° C., 5% aq. KHSO₄ (300 mL) was added to the solution, andthe mixture was extracted with ethyl acetate and dried over anhydrousNa₂SO₄. The solvent was concentrated under reduced pressure, and theconcentrated residue was purified by silica gel column chromatography(n-hexane/ethyl acetate) to give Compound (IIdd) (10.2 g, 72%) as ayellow oil.

Step (ii)

To a solution of cyclohexylmethyl hydrazine dihydro-chloride (948 mg,4.7 mmol) and K₂CO₃ (1.43 g, 19.4 mmol) in ethanol (10 mL) was added asolution of the Compound (IIdd): (1.00 g, 4.7 mmol) in ethanol (15 mL)at room temperature, and the reaction mixture was stirred at roomtemperature for 1 hour and then at 50° C. for 2 hours. The mixture wascooled to room temperature, water was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed with sat. aq.NaHCO₃ and brine, and then dried over anhydrous Na₂SO₄. The solvent wasevaporated under reduced pressure, and the concentrated residue waspurified by silica gel column chromatography (n-hexane/ethyl acetate) togive Compound (IIIdd) (923 mg, 61%) as a pale-yellow solid.

Step (iii)

To a solution of Compound (IIIdd) (88 mg, 0.27 mmol) and pyridine (65mg, 0.82 mmol) in dichloromethane (3 mL) was added benzoyl chloride (46mg, 0.33 mmol) at room temperature, and the reaction mixture was stirredat room temperature overnight. The reaction solution was diluted withethyl acetate, washed with 5% aq. KHSO₄, sat. aq. NaHCO₃ and brine, anddried over anhydrous Na₂SO₄. The solvent was evaporated under reducedpressure, and the concentrated residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give Compound (IVdd) (105 mg,90%) as a yellow oil.

Step (iv)

To a solution of the Compound (IVdd) (63 mg, 0.15 mmol) in THF (3 mL)was added borane-dimethyl sulfide complex (0.59 mmol) at 0° C., and thereaction solution was stirred at 70° C. for 3.5 hours. The reactionsolution was cooled to 0° C., methanol was added thereto, and themixture was heated under reflux for 30 minutes. The mixture was cooledto room temperature, the solvent was evaporated under reduced pressure,to the concentrated residue was added 5% aq. KHSO₄, and the mixture wasextracted with ethyl acetate. The combined organic layers weresubsequently washed with sat. aq. NaHCO₃ and brine, and then dried overanhydrous Na₂SO₄. The solvent was evaporated under reduced pressure, andthe concentrated residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give Compound (Vdd) (31 mg,51%) as a colorless oil.

Step (v)

To a solution of the Compound (Vdd) (31 mg, 0.075 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction solution was stirred at room temperature for 25minutes. The solvent was evaporated under reduced pressure, and theconcentrated residue was purified by adding a small amount of diethylether and removing the supernatant by decantation to give the titleCompound (VIdd) (30 mg, quantitative) as a white powder.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.90-1.25 (5H, m), 1.50-1.90 (6H, m), 2.50(3H, br s), 3.78 (2H, d, J=7.3 Hz), 3.82-3.90 (2H, m), 4.20 (2H, s),5.39 (1H, s), 5.80 (2H, br s), 7.20-7.36 (5H, m), 8.87 (2H, br s).

Obs MS [M+1]: 313.8

Example 358N-Benzyl-1-(cyclohexylmethyl)-N-methyl-3-[(methylamino)-methyl]-1H-pyrazol-5-aminedihydrochloride

Step (i)

To a solution of the Compound (Vdd) prepared in Step (iv) of Example 357(47 mg, 0.11 mmol) in DMF (1 mL) were added sodium hydride (60% oilysuspension, 6.8 mg, 0.17 mmol) and methyl iodide (24 mg, 0.17 mmol) atroom temperature, and the reaction solution was stirred at roomtemperature overnight. To the solution was added 5% aq. KHSO₄, and themixture was extracted with ethyl acetate. The combined organic layerswere washed with water and brine, and then dried over anhydrous Na₂SO₄.The solvent was evaporated under reduced pressure, and the concentratedresidue was purified by silica gel column chromatography (n-hexane/ethylacetate) to give Compound (Iee) (41 mg, 86%) as a colorless oil.

Step (ii)

To a solution of the Compound (Iee) (41 mg, 0.097 mmol) in chloroform(0.5 mL) was added 4 mol/L HCl/1,4-dioxane (1 mL) at room temperature,and the reaction solution was stirred at room temperature for 1 hour.The solvent was evaporated under reduced pressure to give the titleCompound (IIee) (44 mg, quantitative) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃) δ: 0.90-1.05 (2H, m), 1.10-1.30 (3H, m),1.43-1.55 (2H, m), 1.60-1.80 (3H, m), 1.95-2.10 (1H, m), 2.67 (3H, brs), 2.73 (3H, s), 3.90 (2H, d, J=6.0 Hz), 4.13 (2H, s), 4.24 (2H, br s),6.57 (1H, s), 7.23-7.40 (5H, m), 10.12 (2H, br s).

Obs MS [M+1]: 327.5

Examples 359 to 368

The compounds of Examples 359 to 368 as shown in Table 16 were preparedin the same manner as in Example 198 except that a corresponding benzylchloride or benzyl bromide was used.

TABLE 16

Ex. X Y Obs MS [M + 1] 359□ H 4′-Et 336.4 360□ H 4′-i-Pr 350.4 361□ H4′-tBu 364.5 362□ H 2′-F, 4′-Me 340.4 363□ H 4′-CHF₂O 374.3 364□ 2,5-F4′-Et 372.3 365□ 2,5-F 4′-i-Pr 386.3 366□ 2,5-F 4′-t-Bu 400.3 367□ 2,5-F2′-F, 4′-Me 376.5 368□ 2,5-F 4′-CHF₂O 410.4

Examples 369 to 402

The compounds of Examples 369 to 402 as shown in Table 17 were preparedin the same manner as in Examples 20 to 40 except that the compounds ofReference Examples 20, 21, 22, 24, 78 and a corresponding benzylchloride or benzyl bromide were used.

TABLE 17

Ex. R X Y Z Salt Obs MS [M + 1] 369□ a 4-F H H TFA salt 292.3 370□ a 2-F4-F H Free base 310.5 371□ a 2-Cl 4-F H Free base 326.4 372□ a 2-Me 4-FH Free base 306.5 373□ a 2-F 5-Me H Free base 306.5 374□ a 2-F 4-F 5-FHydrochloride 328.6 375□ b 4-F H H TFA salt 306.5 376□ b 2-F 4-F H Freebase 324.6 377□ b 2-Cl 4-F H Free base 340.4 378□ b 2-Me 4-F H TFA salt320.4 379□ b 2-F 5-Me H Free base 320.4 380□ b 2-F 4-F 5-F Hydrochloride342.2 381□ c 2-F H H Hydrochloride 306.4 382□ c 3-F H H Hydrochloride306.4 383□ c 4-F H H Free base 306.4 384□ c 2-Cl H H Free base 322.4385□ c 2-Me H H Free base 302.5 386□ c 3-Me H H Free base 302.5 387□ c4-Me H H Free base 302.5 388□ c 2-CN H H Free base 313.5 389□ c 2-F 4-FH Free base 324.4 390□ c 2-Cl 4-F H TFA salt 340.4 391□ c 2-Me 4-F HFree base 320.5 392□ c 2-F 5-Me H Free base 320.5 393□ d 4-F H H TFAsalt 320.4 394□ d 2-F 4-F H TFA salt 338.4 395□ d 2-Cl 4-F H TFA salt354.6 396□ e 4-F H H Hydrochloride 334.5 397□ e 2-F 4-F H Hydrochloride352.6 398□ e 2-Cl 4-F H Hydrochloride 368.1 399□ e 2-Me 4-F HHydrochloride 348.6 400□ e 2-F 5-F H Hydrochloride 352.6 401□ e 2-F 5-MeH Hydrochloride 348.6 402□ e 2-F 4-F 5-F Hydrochloride 370.5

The variables “a” to “e” in Table 17 represent the groups below:

Example 3751-{1-(2,2-Dimethylpropyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.92 (9H, s), 2.67 (3H, s), 3.73 (2H, s),4.08 (2H, s), 5.01 (2H, s), 5.82 (1H, s), 7.08 (2H, m), 7.35 (2H, m),9.39 (2H, br s).

Example 3761-{5-[(2,4-Difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300. MHz, CDCl₃) δ: 0.93 (9H, s), 1.92 (1H, br s), 2.46 (3H, s),3.67 (2H, s), 3.69 (2H, s), 5.05 (2H, s), 5.60 (1H, s), 6.83-6.94 (2H,m), 7.40 (1H, m).

Example 3771-{5-[(2-Chloro-4-fluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.95 (9H, s), 2.47 (3H, s), 3.67 (2H, s),3.73 (2H, s), 5.10 (2H, s), 5.59 (1H, s), 7.03 (1H, td, J=8.3, 2.6 Hz),7.18 (1H, dd, J=8.4, 2.6 Hz), 7.45 (1H, dd, J=8.5, 6.0 Hz). 1Hunditected (NH)

Example 3781-{1-(2,2-Dimethylpropyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.91 (9H, s), 2.35 (3H, s), 2.71 (3H, s),3.70 (2H, s), 4.11 (2H, s), 5.00 (2H, s), 5.87 (1H, s), 6.87-6.96 (2H,m), 7.30 (1H, m), 9.48 (2H, s).

Example 3791-{1-(2,2-Dimethylpropyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (CDCl₃) δ: 0.94 (9H, s), 2.33 (3H, s), 2.46 (3H, s), 3.66 (2H,s), 3.71 (2H, s), 5.06 (2H, s), 5.59 (1H, s), 6.97 (1H, t, J=9.0 Hz),7.13 (1H, m), 7.21 (1H, m). 1H unditected (NH)

Example 3801-{1-(2,2-Dimethylpropyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 0.93 (9H, s), 2.64 (3H, s), 3.74 (2H, s),4.13 (2H, s), 5.08 (2H, s), 6.24 (1H, s), 7.00 (1H, m), 7.30 (1H, m),9.88 (2H, br s).

Example 3811-{5-[(2-Fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.90 (6H, d, J=6.6 Hz), 1.52 (1H, m), 1.72(2H, q, J=7.2 Hz), 2.73 (3H, t, J=5.1 Hz), 4.10 (2H, t, J=7.4 Hz), 4.31(2H, s), 5.29 (2H, s), 6.67 (1H, s), 7.13 (1H, t, J=9.3 Hz), 7.21 (1H,t, J=7.4 Hz), 7.38-7.49 (2H, m), 10.22 (2H, br s).

Example 3821-{5-[(3-Fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.52 (1H, m), 1.65(2H, q, J=7.2 Hz), 2.62 (3H, s), 3.98 (2H, t, J=7.3 Hz), 4.11 (2H, s),5.10 (2H, s), 6.18 (1H, s), 7.03-7.18 (3H, m), 7.36 (1H, m), 9.82 (2H,s).

Example 3831-{5-[(4-Fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.90 (6H, d, J=6.3 Hz), 1.53 (1H, m), 1.63(2H, m), 2.46 (3H, s), 3.64 (2H, s), 3.92 (2H, t, J=7.4 Hz), 5.01 (2H,s), 5.52 (1H, s), 7.08 (2H, t, J=8.2 Hz), 7.36 (2H, m). 1H unditected(NH)

Example 3891-{5-[(2,4-Difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (6H, d, J=6.6 Hz), 1.53 (1H, m), 1.63(2H, m), 1.83 (1H, br s), 2.46 (3H, s), 3.66 (2H, s), 3.91 (2H, t, J=7.4Hz), 5.07 (2H, s), 5.58 (1H, s), 6.84-6.93 (2H, m), 7.40 (1H, m).

Example 3901-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.89 (6H, d, J=6.4 Hz), 1.50 (1H, m), 1.62(2H, dt, J=6.8, 6.8 Hz), 2.66 (3H, s), 3.94 (2H, t, J=7.4 Hz), 4.07 (2H,s), 5.11 (2H, s), 5.84 (1H, s), 7.02 (1H, td, J=8.3, 2.5 Hz), 7.19 (1H,dd, J=8.4, 2.6 Hz), 7.43 (1H, dd, J=8.6, 6.1 Hz), 9.46 (2H, br s).

Example 3911-{5-[(4-fluoro-2-methylbenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 MHz, CDCl₃) δ: 0.89 (6H, d, J=6.6 Hz), 1.53 (1H, m), 1.62(2H, m), 1.85 (1H, br s), 2.37 (3H, s), 2.48 (3H, s), 3.67 (2H, s), 3.90(2H, t, J=7.4 Hz), 5.00 (2H, s), 5.59 (1H, s), 6.87-6.96 (2H, m), 7.31(1H, dd, J=8.3, 5.9 Hz).

Example 3921-{5-[(2-fluoro-5-methylbenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (400 NHz, CDCl₃) δ: 0.91 (6H, d, J=6.6 Hz), 1.55 (1H, m), 1.64(2H, dt, J=6.8, 6.8 Hz), 1.75 (1H, br s), 2.35 (3H, s), 2.46 (3H, s),3.65 (2H, s), 3.93 (2H, t, J=7.4 Hz), 5.08 (2H, s), 5.58 (1H, s), 6.97(1H, t, J=9.0 Hz), 7.10-7.14 (1H, m), 7.21 (1H, dd, J=7.0, 1.8 Hz).

Examples 403 to 406

The compounds of Examples 403 to 406 as shown in Table 18 were preparedin the same manner as in Examples 20 to 40 except that the compound ofReference Example 77 and a corresponding benzyl chloride or benzylbromide were used.

TABLE 18

Ex. X Y Z Salt Obs MS [M + 1] 403□ H H H TFA salt 304.0 404□ 2-F 5-F HTFA salt 339.9 405□ 2-F 5-Cl H TFA salt 356.0 406□ 2-F 4-F 5-F Free base358.0

Examples 407 to 426

The compounds of Examples 407 to 426 as shown in Table 19 were preparedin the same manner as in Examples 20 to 40 except that the compounds ofReference Examples 2, 3, 74 and a corresponding benzyl chloride orbenzyl bromide were used.

TABLE 19

Obs MS Ex. R X Y Z Salt [M + 1] 407□ f 4-F H H TFA salt 289.9 408□ f 2-F4-F H TFA salt 307.9 409□ f 2-Cl 4-F H TFA salt 323.9 410□ f 2-Me 4-F HTFA salt 303.9 411□ f 4-F 5-Me H TFA salt 304.0 412□ f 2-F 4-F 5-F TFAsalt 325.9 413□ g 4-F H H Free base 304.5 414□ g 2-F 4-F H Hydrochloride322.7 415□ g 2-Cl 4-F H Free base 338.4 416□ g 2-Me 4-F H Hydrochloride318.4 417□ g 2-F 5-Me H Hydrochloride 318.3 418□ g 2-F 4-F 5-F TFA salt340.4 419 h 4-F H H Free base 304.4 420 h 2-F 4-F H Hydrochloride 321.4421 h 2-Cl 4-F H TFA salt 338.4 422 h 2-Me 4-F H TFA salt 318.4 423 h2-F 5-F H Hydrochloride 322.5 424 h 2-F 5-Cl H Hydrochloride 338.4 425 h2-F 5-Me H Hydrochloride 318.4 426 h 2-F 4-F 5-F TFA salt 340.4

The variables “f” to “h” in the table above represent the groups below:

Example 423

¹H-NMR (300 MHz, CDCl₃) δ: −0.02 (2H, m), 0.38 (2H, m), 0.60 (1H, m),1.63 (2H, m), 2.63 (3H, s), 4.00 (2H, t, J=6.7 Hz), 4.11 (2H, s), 5.13(2H, s), 6.17 (1H, s), 7.02-7.10 (2H, m), 7.21 (1H, m), 9.81 (2H, br s).

Example 424

¹H-NMR (300 MHz, CDCl₃) δ: −0.02 (2H, m), 0.38 (2H, m), 0.60 (1H, m),1.63 (2H, m), 2.63 (3H, s), 4.00 (2H, t, J=6.5 Hz), 4.11 (2H, s), 5.11(2H, s), 6.16 (1H, s), 7.06 (1H, t, J=9.0 Hz), 7.32 (1H, m), 7.42 (1H,m), 9.78 (2H, br s).

Example 425

¹H-NMR (300 MHz, CDCl₃) δ: −0.03 (2H, m), 0.36 (2H, m), 0.59 (1H, m),1.64 (2H, m), 2.34 (3H, s), 2.66 (3H, s), 4.05 (2H, t, J=6.3 Hz), 4.16(2H, s), 5.13 (2H, s), 6.30 (1H, s), 6.98 (1H, t, J=9.0 Hz), 7.15 (1H,m), 7.23 (1H, m), 9.90 (2H, br s).

Example 426

¹H-NMR (CDCl₃) δ: −0.05 (2H, m), 0.38 (2H, m), 0.58 (1H, m), 1.62 (2H,m), 2.67 (3H, s), 4.01 (2H, t, J=7.0 Hz), 4.07 (2H, s), 5.05 (2H, s),5.84 (1H, s), 6.99 (1H, td, J=9.6, 6.4 Hz), 7.26 (1H, m), 9.48 (2H, brs).

Examples 427 to 434

The compounds of Examples 427 to 434 as shown in Table 20 were preparedin the same manner as in Examples 20 to 40 except that the compounds ofReference Examples 69 and 70, and a corresponding benzyl chloride orbenzyl bromide were used.

TABLE 20

Ex. n X Y Obs MS [M + 1] 427□ 1 2-Cl 4-F 382.3 428□ 1 2-F 5-F 366.3 429□1 2-F 4-Cl 382.3 430□ 2 H H 344.4 431□ 2 2-F 4-F 380.5 432□ 2 2-Cl 4-F396.3 433□ 2 2-F 5-F 380.5 434□ 2 2-F 5-Cl 396.3

Example 4351-(2-{5-[(5-Chloro-2-fluorobenzyl)oxy]-3-[(methylamino)-methyl]-1H-pyrazol-1-yl}ethyl)cyclopentanolhydrochloride

Step (i)

To a solution of the Compound (IVmm) in Reference Example 79 (100 mg,0.30 mmol) and cesium carbonate (163 mg, 0.50 mmol) in acetonitrile (1.2mL) was added 2-fluoro-5-chlorobenzyl chloride (70 μL, 0.44 mmol) atroom temperature, and the reaction mixture was stirred at roomtemperature for 4 days. The mixture was diluted with ethyl acetate, thesalt was filtered off, the solvent was evaporated under reducedpressure, and the concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:2) to give Compound (Irr) (53mg, 37%) as a colorless oil.

Step (ii)

To a solution of the Compound (Irr) (21 mg, 0.044 mmol) in chloroform(0.4 mL) was added 4 N HCl-1,4-dioxane (0.6 mL) at room temperature, andthe reaction mixture was stirred at room temperature for 50 minutes. Thesolvent was evaporated under reduced pressure, to the concentratedresidue was added diethyl ether, and the precipitate was collected byfiltration and dried under reduced pressure to give the title Compound(IIrr) (16 mg, 87%) as a light brown solid.

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (2H, m), 1.61 (2H, m), 1.80 (4H, m),2.03 (2H, t, J=6.5 Hz), 2.64 (3H, s), 4.08 (2H, s), 4.14 (2H, t, J=6.7Hz), 5.12 (2H, s), 6.15 (1H, s), 7.06 (1H, t, J=9.0 Hz), 7.32 (1H, m),7.43 (1H, m), 9.79 (2H, br s). 1H unditected (OH)

Example 4361-(2-{5-[(2,5-Difluorobenzyl)oxy]-3-[(methylamino)methyl]-1H-pyrazol-1-yl}ethyl)cyclopentanolhydrochloride

The above compound was prepared in the same manner as in Example 435.

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (2H, m), 1.61 (2H, m), 1.78 (2H, m),2.04 (2H, m), 2.33 (2H, m), 2.64 (3H, s), 4.09 (2H, s), 4.16 (2H, m),5.14 (2H, s), 6.18 (1H, s), 7.03-7.09 (2H, d, m), 7.18 (1H, m), 9.81(2H, br s). 1H unditected (OH)

Example 4371-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-[2-(1-methoxycyclo-pentyl)ethyl]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Step (i)

To a solution of the Compound (Irr) in Example 435 (38 mg, 0.079 mmol)in dimethylformamide (0.4 mL) was added sodium hydride (55% suspension,12 mg, 0.28 mmol) at room temperature. To the solution was further addedmethyl iodide (20 μL, 0.31 mmol) at room temperature, and the reactionmixture was stirred at room temperature overnight. To the mixture wasadded 5% aq. KHSO₄, the mixture was extracted with ethyl acetate, theorganic layer was dried over anhydrous Na₂SO₄, and the solvent wasevaporated under reduced pressure. The concentrated residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=1:2) to giveCompound (Iss) (26 mg, 66%) as a pale-yellow oil.

Step (ii)

The title Compound (IIss) was prepared in the same manner as in Step (V)of Example 1.

¹H-NMR (300 MHz, CDCl₃) δ: 1.47 (2H, m), 1.55-1.74 (4H, m), 1.83 (2H,m), 2.02 (2H, m), 2.63 (3H, t, J=5.0 Hz), 3.13 (3H, s), 4.01 (2H, m),4.09 (2H, s), 5.12 (2H, s), 6.15 (1H, s), 7.05 (1H, t, J=9.0 Hz),7.29-7.34 (1H, m), 7.45 (1H, dd, J=6.2, 2.4 Hz), 9.82 (2H, br s).

Example 4381-{5-[(2,5-Difluorobenzyl)oxy]-1-[2-(l-methoxycyclopentyl)-ethyl]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

The above compound was prepared in the same manner as in Example 437.

¹H-NMR (300 MHz, CDCl₃) δ: 1.39 (2H, m), 1.62 (2H, m), 1.67 (2H, m),1.83 (2H, m), 2.02 (2H, m), 2.62 (3H, t, J=5.0 Hz), 3.12 (3H, s), 4.01(2H, m), 4.09 (2H, s), 5.13 (2H, s), 6.15 (1H, s), 7.00-7.11 (2H, dd,m), 7.18 (1H, m), 9.82 (2H, br s).

Examples 439 to 449

The compounds of Examples 439 to 449 as shown in Table 21 were preparedin the same manner as in Examples 20 to 40 except that the compound ofReference Examples 80 to 82 and a corresponding benzyl chloride orbenzyl bromide were used.

TABLE 21

Obs MS Ex. n X Y Z Salt [M + 1] 439 1 H H H TFA salt 339.9 440 1 4-F H HTFA salt 358.0 441 1 2-F 5-F H TFA salt 392.0 442 1 2-F 5-Cl H TFA salt376.0 443 1 2-F 4-F 5-F Hydrochloride 394.0 444 2 2-F 5-Cl HHydrochloride 406.0 445 3 H H H Hydrochloride 368.2 446 3 4-F H HHydrochloride 386.4 447 3 2-F 5-F H Hydrochloride 404.6 448 3 2-F 5-Cl HHydrochloride 420.2 449 3 2-F 4-F 5-F Hydrochloride 422.3

Example 4391-[5-(Benzyloxy)-1-{[1-(trifluoromethyl)cyclopropyl]-methyl}-1H-pyrazol-3-yl]-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.82-0.91 (m, 2H), 0.97-1.10 (m, 2H), 2.61(s, 3H), 4.02 (s, 2H), 4.16 (s, 2H), 5.06 (s, 2H), 5.77 (s, 1H),7.32-7.48 (m, 5H), 9.56 (br s, 2H).

Example 4401-(5-[(4-Fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)cyclo-propyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.82-0.92 (m, 2H), 0.97-1.08 (m, 2H), 2.62(s, 3H), 4.03 (s, 2H), 4.15 (s, 2H), 5.02 (s, 2H), 5.77 (s, 1H), 7.08(t, J=8.6 Hz, 2H), 7.37 (dd, J=8.6, 5.3 Hz, 2H), 9.51 (br s, 2H).

Example 4411-(5-[(2,5-Difluorobenzyl)oxy]-1-{[1-(trifluoromethyl)-cyclopropyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.83-0.93 (m, 2H), 0.97-1.06 (m, 2H), 2.63(s, 3H), 4.04 (s, 2H), 4.17 (s, 2H), 5.10 (s, 2H), 5.81 (s, 1H),6.99-7.19 (m, 3H), 9.51 (br s, 2H).

Example 4421-(5-[(5-Chloro-2-fluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)cyclopropyl]-methyl}-1H-pyrazol-3-yl)-N-methyl-methanaminetrifluoroacetate

¹H-NMR (300 MHz, CDCl₃) δ: 0.84-0.94 (m, 2H), 0.99-1.08 (m, 2H), 2.63(s, 3H), 4.04 (s, 2H), 4.17 (s, 2H), 5.09 (s, 2H), 5.82 (s, 1H), 7.06(t, J=9.1 Hz, 1H), 7.29-7.37 (m, 1H), 7.39-7.46 (m, 1H), 9.56 (br s,2H).

Example 443N-Methyl-1-(5-[(2,4,5-trifluorobenzyl)oxy]-1-{[1-(tri-fluoromethyl)cyclopropyl]methyl}-1H-pyrazol-3-yl)methan-aminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 0.85-0.95 (m, 2H), 0.98-1.07 (m, 2H), 2.60(t, J=5.4 Hz, 3H), 4.09 (br s, 2H), 4.16 (s, 2H), 5.09 (s, 2H), 6.14 (s,1H), 7.00 (dt, J=9.5, 6.5 Hz, 1H), 7.28-7.37 (m, 1H), 9.84 (br s, 2H).

Example 444N-methyl-1-(5-[(5-chloro-2-fluorobenzyl)oxy]-1-{[1-(tri-fluoromethyl)cyclobutyl]methyl}-1H-pyrazol-3-yl)methanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.53-2.01 (m, 2H), 2.19-2.37 (m, 4H), 2.62(s, 3H), 4.12 (s, 2H), 4.19 (s, 2H), 5.12 (s, 2H), 6.18 (s, 1H), 7.06(t, J=9.0 Hz, 1H), 7.32-7.41 (m, 2H), 9.83 (br s, 2H).

Example 4451-[5-(Benzyloxy)-1-{[1-(trifluoromethyl)cyclopentyl]-methyl}-1H-pyrazol-3-yl]-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.36-1.77 (m, 4H), 1.80-2.08 (m, 4H), 2.61(s, 3H), 4.09 (s, 4H), 5.09 (s, 2H), 6.09 (s, 1H), 7.35-7.46 (m, 5H),9.56 (br s, 2H).

Example 4461-(5-[(4-Fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)cyclo-pentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.36-1.77 (m, 4H), 1.79-2.05 (m, 4H), 2.61(s, 3H), 3.96-4.19 (m, 4H), 5.06 (s, 2H), 6.13 (s, 1H), 7.09 (t, J=8.3Hz, 2H), 7.32-7.44 (m, 2H), 9.73 (br s, 2H).

Example 4471-(5-[(2,5-Difluorobenzyl)oxy]-1-{[1-(trifluoromethyl)-cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.39-1.73 (m, 4H), 1.80-2.07 (m, 4H), 2.62(s, 3H), 4.09 (s, 4H), 5.13 (s, 2H), 6.15 (s, 1H), 7.01-7.22 (m, 3H),9.82 (br s, 2H).

Example 4481-(5-[(5-Chloro-2-fluorobenzyl)oxy]-1-{[1-(trifluoro-methyl)cyclopentyl]-methyl}-1H-pyrazol-3-yl)-N-methyl-methanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.38-1.71 (m, 4H), 1.78-2.03 (m, 4H), 2.61(s, 3H), 4.09 (s, 4H), 5.12 (s, 2H), 6.15 (s, 1H), 7.06 (t, J=9.0 Hz,1H), 7.29-7.37 (m, 1H), 7.39-7.47 (m, 1H), 9.73 (br s, 2H).

Example 449N-Methyl-1-(5-[(2,4,5-trifluorobenzyl)oxy]-1-{[1-(tri-fluoromethyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)methan-aminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.40-1.73 (m, 4H), 1.81-2.01 (m, 4H), 2.61(s, 3H), 4.07 (s, 2H), 4.10 (s, 2H), 5.08 (s, 2H), 6.15 (s, 1H),6.88-7.08 (m, 2H), 9.78 (br s, 2H).

Examples 450 to 453

The compounds of Examples 450 to 453 as shown in Table 22 were preparedin the same manner as in Examples 20 to 40 except that the compound ofReference Example 11 and a corresponding benzyl chloride or benzylbromide were used.

TABLE 22

Ex. X Y Z Obs MS [M + 1] 450 2-F 4-F H 378.6 451 2-F 5-F H 378.7 452 2-F5-Cl H 394.2 453 2-F 4-F 5-F 396.3

Example 4501-{5-[(2,4-Difluorobenzyl)oxy]-1-(2-oxabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

¹H-NMR (300 MHz, CDCl₃) δ: 1.43-1.68 (6H, m), 1.87-2.05 (3H, m), 2.46(3H, brs), 3.65 (2H, brs), 3.76 (1H, brs), 3.94 (1H, dd, J=13.4, 7.0Hz), 4.06-4.21 (2H, m), 5.08 (2H, s), 5.57 (1H, s), 6.81-6.95 (2H, m),7.37-7.47 (1H, m).

Example 4511-{5-[(2,5-Difluorobenzyl)oxy]-1-(2-oxabicyclo[2.2.2]oct-3-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydro-chloride

¹H-NMR (300 MHz, CD₃OD) δ: 1.48-1.81 (6H, m), 1.86-2.01 (3H, m), 2.70(3H, brs), 3.71 (1H, brs), 4.00 (1H, dd, J=17.3, 9.8 Hz), 4.07 (2H,brs), 4.12-4.22 (2H, m), 5.24 (2H, s), 5.90 (1H, s), 7.10-7.24 (2H, m),7.28-7.35 (1H, m).

Example 4521-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(2-oxabicyclo[2.2.2]-oct-3-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydro-chloride

¹H-NMR (300 MHz, CD₃OD) δ: 1.49-1.78 (6H, m), 1.87-2.03 (3H, m), 2.71(3H, brs), 3.72 (1H, brs), 4.00 (1H, dd, J=17.6, 9.9 Hz), 4.06 (2H,brs), 4.11-4.22 (2H, m), 5.24 (2H, s), 5.89 (1H, s), 7.19 (1H, dd,J=9.2, 9.2 Hz), 7.38-7.45 (1H, m), 7.56 (1H, dd, J=6.2, 2.6 Hz).

Example 453N-Methyl-1-{1-(2-oxabicyclo[2.2.2]oct-3-ylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

¹H-NMR (300 MHz, CD₃OD) δ: 1.47-1.80 (6H, m), 1.85-2.02 (3H, m), 2.71(3H, brs), 3.70 (1H, brs), 3.98 (1H, dd, J=17.3, 9.6 Hz), 4.06 (2H,brs), 4.10-4.21 (2H, m), 5.21 (2H, s), 5.90 (1H, s), 7.21-7.33 (1H, m),7.48-7.58 (1H, m).

Examples 454 to 469

The compounds of Examples 454 to 469 as shown in Table 23 were preparedin the same manner as in Examples 20 to 40 except that the compounds ofReference Examples 33, 83 and 84, and a corresponding benzyl chloride orbenzyl bromide were used.

TABLE 23

Obs MS Ex. R X Y Z Salt [M + 1] 454 c 2-Cl H H Hydrochloride 336.7 455 c2-Me H H Hydrochloride 316.5 456 c 3-F H H Hydrochloride 320.5 457 c 2-F5-F H Hydrochloride 338.4 458 c 2-Me 5-F H Free base 334.6 459 c 2-F5-MeO H Hydrochloride 350.8 460 c 2-F 4-F 5-F Hydrochloride 356.3 461 j2-F 5-F H Hydrochloride 352.7 462 j 2-F 5-Cl H Hydrochloride 368.1 463 j2-F 5-MeO H Hydrochloride 364.6 464 j 2-F 4-F 5-F Hydrochloride 370.4465 k 2-F 4-F H Hydrochloride 364.5 466 k 2-F 5-Cl H Hydrochloride 380.4467 k 2-Me 5-F H Hydrochloride 360.5 468 k 2-MeO 5-F H Free base 376.6469 k 2-F 4-F 5-F Hydrochloride 382.4

The variable “c” in Table 23 is the same as defined in Table 17, and thevariables “j” and “k” in Table 23 represent the groups below:

Example 470(−)-1-{1-(1-Cyclohexylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamineExample 471(+)-1-{1-(1-Cyclohexylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine

wherein ** is an asymmetric carbon, and the compound containing it meansan optically active substance.

Compound (Itt) in Example 303 was purified by liquid columnchromatography under the following conditions. Compound (IItt) waseluted at a shorter retention time and then Compound (IIItt) was elutedlater, which were both given as a light-brown oil. The conditions of theliquid column chromatography are as follows:

Column; CHIRALCEL (trademark) OZ-H 5 cm I.D.×25 cm

Mobile phase; acetonitrile:diisopropylamine=100:0.1 (v/v)

Flow rate; 47 mL/min

Temperature; 30° C.

Detected UV wavelength; 268 nm

Compound (IItt):

¹H-NMR (300 MHz, CDCl₃) δ: 0.83 (1H, m), 0.96 (1H, m), 1.06-1.33 (4H,m), 1.41 (3H, d, J=7.0 Hz), 1.57-1.90 (6H, m), 2.46 (3H, s), 3.66 (2H,s), 3.92-4.02 (1H, m), 5.09 (2H, s), 5.55 (1H, s), 6.98-7.17 (3H, m).

Specific rotation; [α]D²⁶−17.3 (c. 1.47, CHCl₃)

Compound (IIItt):

Specific rotation; [α]D²⁶+19.2 (c. 1.03, CHCl₃)

Example 472(−)-1-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(1-cyclohexyl-ethyl)-1H-pyrazol-3-yl}-N-methylmethanamineExample 473(+)-1-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(1-cyclohexyl-ethyl)-1H-pyrazol-3-yl}-N-methylmethanamine

wherein ** is as defined above.

Compound (Iuu) in Example 304 was purified by liquid columnchromatography under the following conditions. Compound (IIuu) waseluted at a shorter retention time and then Compound (IIIuu) was elutedlater, which were both given as a light-brown oil. The conditions of theliquid column chromatography are as follows:

Column; CHIRALCEL (trademark) OZ-H, 5 cm I.D.×25 cm

Mobile phase; acetonitrile:diisopropylamine=100:0.1 (v/v)

Flow rate; 47 mL/min

Temperature; 25° C.

Detected UV wavelength; 272 nm

Compound (IIuu):

¹H-NMR (300 MHz, CDCl₃) δ: 0.81 (1H, m), 0.96 (1H, m), 1.06-1.28 (4H,m), 1.41 (3H, d, J=6.8 Hz), 1.48-1.90 (6H, m), 2.46 (3H, s), 3.65 (2H,s), 3.96 (1H, m), 5.08 (2H, s), 5.54 (1H, s), 7.05 (1H, t, J=9.0 Hz),7.29 (1H, m), 7.41 (1H, dd, J=6.2, 2.8 Hz).

Specific rotation; [α]D²⁶−13.1 (c. 1.13, CHCl₃)

Compound (IIIuu):

Specific rotation; [α]D²⁶+11.6 (c. 2.04, CHCl₃)

Example 474(−)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

wherein ** is as defined above.

Step (i)

Compound (Iww) prepared in the same manner as in Examples 92 to 114 waspurified by liquid column chromatography. Compound (IIww) was eluted ata shorter retention time and then Compound (IIIww) was eluted later,which were both given as a light-brown oil. The conditions of the liquidcolumn chromatography are as follows:

Column; CHIRALCEL (trademark) OZ-H, 5 cm I.D.×25 cm

Mobile phase; acetonitrile

Flow rate; 47 mL/min

Temperature; 40° C.

Detected UV wavelength; 271 nm

Compound (IIww):

Specific rotation; [α]D²⁶−5.0 (c. 1.04, CHCl₃)

Compound (IIIww):

Specific rotation; [α]D²⁶+3.7 (c. 1.07, CHCl₃)

Step (ii)

Compound (IVww) was prepared in the same manner as in Step (V) ofExample 1 except that the Compound (IIww) was used.

¹H-NMR (300 MHz, CDCl₃) δ: 1.29 (1H, m), 1.43-1.67 (4H, m), 1.84 (1H,m), 2.62 (3H, s), 3.36 (1H, t, J=10.8 Hz), 3.67 (1H, m), 3.88 (1H, dd,J=14.1, 4.4 Hz), 3.97 (1H, m), 4.05 (1H, m), 4.09 (2H, s), 5.13 (2H, s),6.11 (1H, s), 7.04 (1H, t, J=9.0 Hz), 7.30 (1H, m), 7.47 (1H, dd, J=6.0,2.5 Hz), 9.78 (2H, br s).

Specific rotation; [α]D²⁶−6.6 (c. 1.21, CHCl₃)

Example 475(+)-1-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

wherein ** is as defined above.

Compound (Vww) was prepared in the same manner as in Step (V) of Example1 except that the Compound (IIIww) was used.

¹H-NMR (300 MHz, CDCl₃) δ: 1.28 (1H, m), 1.41-1.65 (4H, m), 1.84 (1H,m), 2.61 (3H, s), 3.36 (1H, t, J=11.1 Hz), 3.66 (1H, m), 3.88 (1H, dd,J=13.9, 4.8 Hz), 3.97 (1H, m), 4.05 (1H, m), 4.09 (2H, s), 5.13 (2H, s),6.11 (1H, s), 7.04 (1H, t, J=9.0 Hz), 7.29 (1H, m), 7.47 (1H, dd, J=6.1,2.6 Hz), 9.79 (2H, br s).

Specific rotation; [α]D²⁶+6.0 (c. 1.14, CHCl₃)

Example 476(−)-1-{1-(2-Cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamineExample 477(+)-1-{1-(2-Cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine

wherein ** is as defined above.

A free form of the Compound (Ixx) in Example 315 was purified by liquidcolumn chromatography under the following conditions. Compound (IIxx)was eluted at a shorter retention time and then Compound (IIIxx) waseluted later, which were both given as a light-brown oil. The conditionsof the liquid column chromatography are as follows:

Column; CHIRALPAK (trademark) AY-H, 5 cm I.D.×25 cm

Mobile phase; n-hexane:ethanol:diethylamine=95:5:0.1 (v/v)

Flow rate; 47 mL/min

Temperature; 40° C.

Detected UV wavelength; 268 nm

Compound (IIxx):

¹H-NMR (300 MHz, CDCl₃) δ: 1.09 (2H, m), 1.35 (3H, d, J=6.8 Hz),1.44-1.63 (5H, m), 1.69-1.83 (5H, m), 2.37 (3H, s), 3.64 (1H, q, J=6.7Hz), 3.94 (2H, t, J=7.2 Hz), 5.10 (2H, s), 5.52 (1H, s), 6.98-7.11 (2H,m), 7.15 (1H, m).

Specific rotation; [α]D²⁶−25.4 (c. 1.42, CHCl₃)

Compound (IIIxx):

Specific rotation; [α]D²⁶+25.0 (c. 1.60, CHCl₃)

Example 4781-{1-(3-Methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

The title compound was prepared in the same manner as in Example 347.

¹H-NMR (400 MHz, CDCl₃) δ: 0.85 (6H, t, J=6.4 Hz), 1.42-1.52 (1H, m),1.64-1.74 (2H, m), 4.15 (2H, br s), 4.60 (2H, br s), 5.37 (2H, br s),6.90-7.00 (2H, m), 7.48-7.52 (1H, m), 9.06 (3H, br s).

Example 4791-{1-(Cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine

Step (i)

To a solution of Compound (Iyy) prepared in the same manner as in Steps(i) to (iii) of Example 1 (300 mg, 0.99 mmol), triphenylphosphine (310mg, 1.2 mmol) and phthalimide (160 mg, 1.1 mmol) in tetrahydrofuran (5mL) was added diisopropylazodicarboxylate (248 μL, 1.2 mmol) at roomtemperature, and the reaction mixture was stirred at room temperatureovernight. The solvent was evaporated under reduced pressure, theconcentrated residue was purified by silica gel column chromatography(n-hexane ethyl acetate=3:1) to give Compound (IIyy) (550 mg).

Step (ii)

To the Compound (IIyy) (550 mg, equivalent to 0.99 mmol) was addedmethylamine (in 40% methanol, 5 mL), and the reaction mixture wasstirred at 40° C. for 30 minutes. The solvent was evaporated underreduced pressure, and the concentrated residue was purified bysilica-gel chromatography (chloroform:methanol=10:1) to give Compound(IIIyy) (156 mg, 52% in 2 steps) as a light-brown oil.

¹H-NMR (300 MHz, CDCl₃) δ: 1.16-1.34 (m, 2H), 1.43-1.75 (m, 6H),2.30-2.48 (m, 1H), 3.76 (s, 2H), 3.83 (d, J=7.5 Hz, 2H), 5.02 (s, 2H),5.49 (s, 1H), 7.09 (t, J=8.6 Hz, 2H), 7.37 (dd, J=8.6, 5.5 Hz, 2H).

Example 4801-{5-[(4-Fluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

Steps (i) to (ii)

To a solution of 3-methyl-1,3-butanediol (2.5 g, 24 mmol) and4-N,N-dimethylaminopyridine (3.08 g, 25 mmol) in dichloromethane (96 mL)was added dropwise a solution of p-toluene sulfonyl chloride (4.80 g, 25mmol) in dichloro-methane (32 mL) with cooling in a water bath, and thereaction mixture was stirred at room temperature for 22 hours. To themixture was further added triethylamine (3.3 mL, 24 mmol), and thereaction mixture was stirred for 100 minutes. The mixture waspartitioned between water (50 mL) and chloroform (30 mL). The organiclayer was washed with water (50 mL×2) and brine (50 mL), and dried overanhydrous Na₂SO₄. The organic solvent was evaporated under reducedpressure to give a crude product of Compound (Iddd) (6.43 g), which wasused in the next step without further purification.

The resulting Compound (Iddd), di-tert-butyl hydrazinedicarboxylate(5.57 g, 24 mmol) and cesium carbonate (9.38 g, 29 mmol) were dissolvedin dimethyl-formamide (24 mL), and the reaction mixture was stirred at60° C. for 3 hours. The mixture was cooled to room temperature anddiluted with ethyl acetate (100 mL), the salt was filtered off, to thefiltrate was added ethyl acetate (100 mL), and the resultant was washedwith water (40 mL). The solvent was evaporated under reduced pressure,the concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to give Compound (IIddd)(3.40 g, 44%) as a colorless oil.

Steps (iii) to (iv)

To a solution of the Compound (IIddd) (3.40 g, 10.7 mmol) in methanol(11 mL) was added conc. HCl (5.3 mL), and the reaction mixture wasstirred at room temperature for 3 hours. The methanol was evaporatedunder reduced pressure, to the concentrated residue was added toluene,and the solvent was evaporated under reduced pressure (×3) to give acrude product of Compound (IIIddd) (700 mg), which was used in the nextstep without further purification.

The resulting Compound (IIIddd) and triethylamine (1.2 mL, 8.7 mmol)were dissolved in ethanol (7.3 mL), and the mixture was stirred at 45°C. To the mixture was further added a solution of the Compound (IIa) inReference Example 1 (863 mg, 3.3 mmol) in ethanol (2 mL), and thereaction mixture was stirred at 80° C. for 2 hours. The mixture wascooled to room temperature, 5% aq. KHSO₄ was added thereto, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous MgSO₄, the solvent was evaporated under reduced pressure,and the concentrated residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:2--->ethylacetate--->chloroform:methanol=10:1) to give Compound (IVddd) (474 mg,45%) as a pale-yellow solid.

Step (V)

Compound (Vddd) as a pale-yellow oil was prepared in the same manner asin Examples 20 to 40 except that the Compound (IVddd) and 4-fluorobenzylchloride were used.

Step (vi)

To a solution of the Compound (Vddd) (58 mg, 0.14 mmol) and DBU (62 μL,0.41 mmol) in dichloromethane (0.7 mL) was added XtalFluor-E (trademark)(79 mg, 0.35 mmol) at ice temperature, and the reaction mixture wasstirred at ice temperature for 20 minutes and then at room temperaturefor 30 minutes. To the mixture was added sat. aq. NaHCO₃, the mixturewas extracted with chloroform, the organic layer was dried overanhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure.The concentrated residue was purified by PTLC (n-hexane:ethylacetate=1:1) to give Compound (VIddd) (17 mg, 29%) as a colorless oil.

Step (vii)

Compound (VIIddd) was prepared in the same manner as in Step (V) ofExample 1 except that the Compound (VIddd) was used.

¹H-NMR (300 MHz, CDCl₃) δ: 1.35 (6H, d, J=21.3 Hz), 2.06 (2H, dt,J=19.5, 7.5 Hz), 2.61 (3H, s), 4.07 (4H, m), 5.06 (2H, s), 6.13 (1H, s),7.08 (2H, t, J=8.4 Hz), 7.38 (2H, m), 9.77 (2H, br s).

Obs MS [M+1]: 324.6

Examples 481 to 483

The compounds of Examples 481 to 483 were prepared in the same manner asin Example 480.

Example 4811-{5-[(2,5-Difluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.36 (6H, d, J=21.3 Hz), 2.08 (2H, dt,J=19.5, 7.5 Hz), 2.62 (3H, s), 4.09 (4H, m), 5.13 (2H, s), 6.15 (1H, s),7.06 (2H, m), 7.16 (1H, m), 9.80 (2H, br s).

Obs MS [M+1]: 342.3

Example 4821-{5-[(5-Chloro-2-fluorobenzyl)oxy]-1-(3-fluoro-3-methyl-butyl)-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.36 (6H, d, J=21.5 Hz), 2.09 (2H, dt,J=19.5, 7.7 Hz), 2.62 (3H, s), 4.09 (4H, m), 5.12 (2H, s), 6.15 (1H, s),7.06 (1H, t, J=9.0 Hz), 7.32 (1H, m), 7.44 (1H, m), 9.80 (2H, br s).

Obs MS [M+1]: 358.2

Example 4831-{1-(3-Fluoro-3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

¹H-NMR (300 MHz, CDCl₃) δ: 1.36 (6H, d, J=21.5 Hz), 2.08 (2H, dt,J=19.8, 7.7 Hz), 2.63 (3H, s), 4.08 (4H, m), 5.10 (2H, s), 6.15 (1H, s),6.98 (1H, m), 7.31 (1H, m), 9.69 (2H, br s).

Obs MS [M+1]: 360.3

Example 4841-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminemonophosphate

Step (i)

To a solution of Compound (Izz) in Reference Example 85 (48.0 g, 200mmol) and K₂CO₃ (41.8 g, 300 mmol) in dimethylformamide (192 g) wasadded dropwise 2,5-difluorobenzyl chloride (36.0 g, 220 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for5.5 hours. The resultant salt was filtered off and washed withdimethylformamide (48 g). To 73.3 g (i.e. a quarter amount) of theresultant filtrate (293 g in total) was added dropwise water (180 g) at35° C. over 1 hour, and the mixture was stirred for 1 hour at the samecondition and then stirred for 1 hour with cooling to 15° C. Theprecipitate was collected by filtration, washed with a mixed solvent ofdimethylformamide (8.4 g) and water (25 g), further washed with2-propanol (15.6 g×2), and dried under reduced pressure to give Compound(IIzz) (16.6 g, 90%)

Step (ii)

To a suspension of the Compound (IIzz) (35.0 g, 100 mmol) and sodiumborohydride (7.99 g, 210 mmol) in tetra-hydrofuran (175 g) was addeddropwise methanol (30.8 g) at 35° C. to 45° C. over 15 minutes, and thereaction mixture was stirred for 2 hours. The mixture was cooled to roomtemperature, and toluene (262.5 g) was added thereto. To the mixture wasadded dropwise 3.6% HCl (262.5 g) over 15 minutes with keeping thetemperature below 40° C. The organic layer was washed with water (262.5g×2) and concentrated under reduced pressure to give a crude product ofCompound (Iw) (32.1 g).

Steps (iii) to (iv)

To a solution of the Compound (Iw) (5.00 g, 15.5 mmol) and triethylamine(2.35 g, 23 mmol) in tetrahydrofuran (45.5 g) was added dropwisemethanesulfonyl chloride (2.13 g, 18.6 mmol) with keeping thetemperature below 10° C., and the reaction mixture was stirred at around5° C. for 1 hour and then slowly warmed to room temperature. Theprecipitate was filtered off to give a solution of Compound (IIIzz),which was used in the next step without further purification.

To 40% methylamine methanol solution (36 g) was added dropwise thesolution of Compound (IIIzz) at ice temperature over 30 minutes, and thereaction mixture was stirred at the same condition for 1 hour. To themixture were added toluene (50 g) and water (40), the mixture was slowlywarmed to room temperature, and the organic layer was concentrated underreduced pressure. To the concentrated residue (5.09 g) were added2-propanol (39 g) and phosphoric acid (75%, 2.10 g), the mixture washeated to 80° C., the solid was dissolved, and the solution was stirredat 60° C. to 65° C. After a solid was precipitated, the resultant wasstirred at 60° C. to 65° C. for 1 hour. The solution was cooled to 3° C.over 6 hours and stirred at 3° C. for 7 hours. The resulting precipitatewas collected by filtration, washed with cold 2-propanol (5 g), anddried under reduced pressure to give the title Compound (IVzz) (4.81 g,72%) as a white crystalline solid.

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.07-1.30 (m, 2H), 1.35-1.64 (m, 6H),2.15-2.32 (m, 1H), 2.37 (s, 3H), 3.72 (s, 2H), 3.75 (s, 2H), 5.16 (s,2H), 5.91 (s, 1H), 6.96 (br s, 4H), 7.22-7.51 (m, 3H).

Example 4851-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminemonophosphate

To a solution of Compound (Iw) in Example 480 (7.00 g, 21.7 mmol) andtriethylamine (2.64 g, 36.0 mmol) in tetrahydrofuran (28 g) was addeddropwise methanesulfonyl chloride (2.99 g, 26.1 mmol) with ice-cooling.The reaction mixture was stirred at around 5° C. for 1 hour, dilutedwith tetrahydrofuran (8.4 g), and slowly warmed to room temperature. Theprecipitate was filtered off, and the filtrate was used in the next stepwithout further purification. To a suspension of potassium t-butoxide(4.39 g, 39.1 mmol) in tetrahydrofuran (28 g) was added dropwiseN-Boc-methylamine (5.70 g, 43.5 mmol) at room temperature over 15minutes. To the solution was added dropwise the above-obtained filtratewith keeping the internal temperature below 15° C. over 40 minutes, andthe reaction mixture was stirred at below 15° C. for 0.1 hour. Themixture was slowly warmed to room temperature, to the mixture was addeddropwise conc. HCl (36%, 21 g) at room temperature over 5 minutes, andthe mixed solution was stirred at 40° C. for 4 hours. The mixture wascooled to room temperature, and partitioned between 27% aq. NaOH (11.9g) and toluene (17.5 g). The organic layer was washed with water (31.5g), and the solvent was evaporated under reduced pressure. To theconcentrated residue (7.86 g) was added toluene to adjust the totalweight to 32.5 g. To the mixture was further added 2-propanol (63 g).The mixed solution was heated to 50° C., and to the solution was addeddropwise a solution of phosphoric acid (85%, 2.58 g) in 2-propanol (9.10g) at 50° C. over 3 minutes (1.17 g out of the total). To the mixturewere added seed crystals of the title compound (40 mg) at 50° C., andthe remaining 10.52 g of the above-mentioned solution was added dropwisethereto over 1 hour. The mixture was stirred at 50° C. for 30 minutes,cooled at a rate of 20° C./hour, and stirred at 5° C. for 1 hour. Theprecipitate was collected by filtration, washed twice with a mixedsolution of cold toluene (4 g) and 2-propanol (12 g), and dried underreduced pressure to give the title Compound (IVzz) (7.76 g, 83%) as awhite powder.

Example 4861-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminehydrochloride

To a solution of a mixture of Compound (IIIa) in Reference Example 1(108 g, 349 mmol) and cesium carbonate (171 g, 524 mmol) indimethylformamide (1081 mL) was added dropwise a solution of2,5-difluorobenzyl chloride (68.1 g, 419 mmol) in dimethylformamide (81mL). The reaction mixture was stirred at room temperature for 14 hours,water (1729 mL) was added thereto with ice-cooling, and to the mixturewas further added toluene (2579 mL). The organic layer was washed withwater (562 mL) and the toluene was evaporated under reduced pressure togive a concentrated residue (146 g), which was used in the next stepwithout further purification. The residue (146 g) was dissolved inmethanol (394 mL), to the solution was added conc. HCl (36%, 120 g) at50° C., and the reaction mixture was stirred at 50° C. for 1.5 hours.The mixture was cooled to room temperature, the solvent was evaporatedunder reduced pressure, to the concentrated residue was added 2-propanol(394 mL), and the solvent was evaporated under reduced pressure (×3) togive a concentrated residue (182 g) as a light brown solid. To theresidue was added 2-propanol (591 mL). After the solid was dissolved,n-hexane (1183 mL) was added dropwise to the solution at roomtemperature over 1 hour. The mixture was stirred at room temperatureovernight and then with ice-cooling for 3 hours. The precipitate wascollected by filtration, washed with a mixed solution of cold 2-propanol(31 mL) and cold n-hexane (92 mL), and dried under reduced pressure togive the title Compound (IVzz′) (68.7 g, 53%) as a white crystallinesolid.

Example 4871-{1-(Cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanaminemonocitrate

To a solution of a mixture of the Compound (IIIa) in Reference Example 1(10 g, 32 mmol) and cesium carbonate (15.8 g, 48.5 mmol) indimethylformamide (27 mL) was added dropwise a solution of2,5-difluorobenzyl chloride (6.31 g, 38.8 mmol) in dimethylformamide (5mL) at room temperature. The reaction mixture was stirred at roomtemperature for 17 hours, and to the mixture were added water (64 mL)and further toluene (96 mL). The organic layer was washed with water (32mL), the toluene was evaporated under reduced pressure, methanol (20 mL)was added thereto, and the solvent was evaporated under reduced pressure(×3) to give a crude product of Compound (Iaaa) (14.8 g) as a brown oil,which was used in the next step without further purification.

The resulting Compound (Iaaa) was dissolved in methanol (32 mL), to thesolution was added conc. HCl (36%, 9.8 g) at 50° C., and the reactionmixture was stirred at 50° C. for 1.5 hours. The mixture was cooled toroom temperature, the solvent was evaporated under reduced pressure, andthe mixture was partitioned between 20% aq. potassium bicarbonate (25mL) and toluene (80 mL). The organic layer was washed with water (20mL), the solvent was evaporated under reduced pressure, 2-propanol (20mL) was added thereto, and the solvent was evaporated under reducedpressure (×2) to give a free base of the compound (14.5 g). A halfamount of the compound (equivalent to 16.2 mmol) and anhydrous citricacid (3.10 g, 16.2 mmol) were added to 2-propanol (83 mL), and themixture was heated to around 80° C. After the solid was dissolved, thesolution was cooled to 50° C., seed crystals of the title Compound(IVzz″) (5 mg) were added to the solution, and the mixture was stirredfor 2 hours at around 45° C. and then stirred overnight with slowlycooling to room temperature. The mixture was cooled with ice for 2hours, and the precipitate was collected by filtration and dried underreduced pressure to give the title Compound (IVzz″) (6.17 g, 72%) as awhite crystalline solid.

¹H-NMR (300 MHz, CD₃OD) δ: 1.17-1.35 (m, 2H), 1.46-1.69 (m, 6H),2.29-2.47 (m, 1H), 2.68 (s, 3H), 2.72 (d, J=15.4 Hz, 2H), 2.81 (d,J=15.4 Hz, 2H), 3.88 (d, J=7.5 Hz, 2H), 4.06 (s, 2H), 5.22 (s, 2H), 5.90(s, 1H), 7.09-7.32 (m, 3H).

Example 488N-Methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

To a solution of the title Compound (Ibbb) of Reference Example 24 (11.9g, 40 mmol) and cesium carbonate (1.95 g, 60 mmol) in dimethylformamide(123 mL) was added 2,4,5-trifluorobenzyl chloride (8.70 g, 48 mmol) atroom temperature, and the reaction mixture was stirred at roomtemperature for 16 hours. The mixture was partitioned between water (190mL) and toluene (190 mL), the organic layer was washed with water (62mL) and dried over anhydrous MgSO₄, and the solvent was evaporated underreduced pressure. To the resultant was added toluene (39 mL) and thesolvent was evaporated under reduced pressure. To the resultant wasadded methanol (39 mL) and the solvent was evaporated under reducedpressure (×2) to give a crude product of Compound (IIbbb) (18.0 g) as abrown oil (i.e. a concentrated residue), which was used in the next stepwithout further purification.

The residue was dissolved in methanol (38 mL), to the solution was addedconc. HCl (11.7 g) at 50° C., the reaction mixture was stirred at 50° C.for 2 hours, and the solvent was evaporated under reduced pressure. Tothe concentrated residue was added 2-propanol (40 mL), and the solventwas evaporated under reduced pressure (×2). To the resultant was furtheradded 2-propanol (20 mL) and the solvent was evaporated under reducedpressure to give the concentrated residue (17.1 g) as a pale-yellowsolid. To the residue was added 2-propanol (57 mL), the mixture washeated to 50° C., the solid was dissolved, and the solution was slowlycooled to around 30° C. After a solid was precipitated, n-hexane (114mL) was added dropwise thereto at 25° C. to 30° C. over 1 hour. Themixture was stirred at 25° C. to 30° C. for 30 minutes, cooled to 5° C.over 1 hour, and stirred at ice temperature for 1 hour. The resultingprecipitate was collected by filtration, washed with a mixed solution ofcold 2-propanol and n-hexane (1:5, 12 mL), and dried under reducedpressure to give Compound (IIIbbb) as a white solid.

Example 489N-Methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminehydrochloride

Step (i)

To a solution of a mixture of Compound (Iccc) in Reference Example 87(5.00 g, 22 mmol) and K₂CO₃ (4.58 g, 33 mmol) in dimethylformamide (22mL) was added 2,4,5-trifluorobenzyl chloride (4.79 g, 26.5 mmol) at roomtemperature, and the reaction mixture was stirred at room temperaturefor 15 hours. The salt was filtered off and washed withdimethylformamide (15 mL). The filtrate was added dropwise to water (111mL) at 40° C. over 15 minutes. The mixture was stirred at 40° C. for 1hour, cooled to 6° C. over 2 hours, and stirred for 1 hour. Theprecipitate was collected by filtration, and subsequently washed with amixed solution of cold dimethylformamide and water (1:3, 10 mL), cold2-propanol (10 mL), and then n-hexane (20 mL). The resultant was driedunder reduced pressure to give Compound (IIccc) (6.56 g, 80%) as a lightbrown powder.

Step (ii)

To a suspension of lithium aluminum hydride (768 mg, 20 mmol) intetrahydrofuran (20 mL) was added dropwise a solution of theabove-obtained compound (5.00 g, 13.5 mmol) in tetrahydrofuran (12 mL)with keeping the internal temperature below 15° C. over 15 minutes, andthe reaction mixture was stirred at the same condition for 1 hour. Tothe mixture was subsequently added water (0.77 mL), 15% NaOH (0.77 mL)and then water (2.31 mL). The precipitate was filtered off throughCelite, the filtrate was concentrated under reduced pressure, to theconcentrated residue (4.22 g) was added toluene (15 mL), and the solventwas evaporated under reduced pressure (×2). To the concentrated residuewere added toluene (25 mL) and n-hexane (45 mL), the mixture was stirredfor 1 hour at 40° C. (internal temperature), and a precipitate wasformed. The resultant was cooled to ice temperature over 2 hours andstirred for 1 hour. The precipitate was collected by filtration, washedwith a mixed solution of toluene and n-hexane (1:4, 4 mL), and driedunder reduced pressure to give Compound (IIIccc) (3.76 g, 85%) as awhite solid.

Step (iii)

To a solution of the Compound (IIIccc) (5.00 g, 15 mmol) andtriethylamine (2.54 mL, 18 mmol) in tetra-hydrofuran (30 mL) was addeddropwise methanesulfonyl chloride (1.3 mL, 16.8 mmol) with keeping theinternal temperature below 15° C. over 15 minutes. The reaction mixturewas stirred for 2 hours with slowly warming to room temperature. Thesalt was filtered off and washed with tetrahydrofuran (5 mL, ×2). To theresultant filtrate was added dropwise 40% methylamine/methanol (40 mL)at 5° C. to 8° C. over 15 minutes, and the reaction mixture was stirredfor 1 hour. To the mixture were added toluene (40 mL) and water (30 mL),the mixture was warmed to room temperature, and the organic layer wasconcentrated under reduced pressure. To the concentrated residue wasadded 2-propanol (15 mL), and the mixture was concentrated under reducedpressure (×2). The concentrated residue (5.54 g) was dissolved in2-propanol (15 mL), to the solution was added 36% conc. HCl (3.08 g,30.5 mmol) at room temperature, and the solvent was evaporated underreduced pressure. To the concentrated residue was added 2-propanol (15mL), and the solvent was concentrated under reduced pressure (×2). Tothe concentrated residue (6.16 g) was added 2-propanol (20 mL), theresultant was heated to 50° C. (internal temperature), and the solid wasdissolved. The solution was cooled to 35° C. to form a precipitate, andn-hexane (40 mL) was added dropwise thereto over 1 hour at around 35° C.(internal temperature). The mixture was stirred at 35° C. for 1 hour,cooled to 5° C. (internal temperature) over 2 hours, and stirred at thesame condition for 1 hour. The precipitate was collected by filtration,washed with a mixed solution of cold 2-propanol and n-hexane (1:4, 5mL), and dried under reduced pressure to give the title Compound(IIIbbb) (3.22 g, 56%) as a white crystalline solid.

Example 490N-Methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminemonophosphate

To the Compound (IIIbbb) in Example 488 (3.6 g, 9.5 mmol) was added 10%aq. K₂CO₃ (50 mL), and the mixture was extracted with chloroform (100mL). The organic layer was dried over anhydrous Na₂SO₄, the solvent wasevaporated under reduced pressure, and the concentrated residue waspurified by silica gel column chromatography (chloroform methanol=10:1)to give a free base of Compound (IIIbbb) (3.02 g) as a light-brown oil.A solution of a mixture of the free base of Compound (IIIbbb) (200 mg,0.59 mmol) and phosphoric acid (75%, 77 mg, 0.59 mmol) in 2-propanol (2mL) was stirred at 80° C. for 30 minutes, and then stirred with slowlycooling to room temperature. The resulting precipitate was collected byfiltration and dried under reduced pressure to give the title compound(219 mg, 84%) as a white crystalline solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.82 (6H, d, J=6.3 Hz), 1.38-1.42 (1H, m),1.49 (2H, dt, J=7.1 Hz, J=7.1 Hz), 2.37 (3H, s), 3.72 (2H, s), 3.83 (2H,t, J=7.1 Hz), 5.14 (2H, s), 5.93 (1H, s), 6.13 (4H, br), 7.62-7.69 (1H,m), 7.74-7.78 (1H, m).

Example 491N-Methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)-oxy]-1H-pyrazol-3-yl}methanaminemonocitrate

To a free base of Compound (IIIbbb) prepared in the same manner as inExample 490 (equivalent to 1.0 mmol) were added a solution of citricacid monohydrate (210 mg, 1.0 mmol) in water (1.5 mL), and further added2-propanol (20 mL). The solvent was evaporated under reduced pressure(×2) to give a concentrated residue (546 mg). To the residue was added2-propanol (4 mL), and the mixture was stirred at 50° C. After the solidwas dissolved, the solution was slowly cooled to room temperature. Tothe solution was added dropwise n-hexane (8 mL) with ice-cooling, andthe mixture was stirred at ice temperature for 30 minutes. Theprecipitate was collected by filtration, washed with a mixed solution ofcold n-hexane/2-propanol (2:1, 5 mL), and dried under reduced pressureto give the title compound (325 mg) as a white crystalline solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.83 (6H, d, J=6.4 Hz), 1.38-1.45 (1H, m),1.51 (2H, dt, J=6.8 Hz, J=6.8 Hz), 2.44-2.56 (7H, m), 3.31 (4H, br),3.87 (2H, t, J=6.8 Hz), 3.96 (2H, s), 5.17 (2H, s), 5.89 (1H, s),7.63-7.77 (2H, m), 10.62 (1H, br).

Test Example 1: [³H] Citalopram Binding Assay to Evaluate HumanSerotonin Reuptake Inhibitory Action 1-1. Preparation of the Cells andMembrane Preparations

In the experiment, human serotonin transporter (h-SERT) was expressed inCHO cells (h-SERT/CHO). The cells were incubated with F12 containing 10%FCS, 500 μg/mL Geneticin and 100 U/mL penicillin—100 μg/mL streptmycin(all manufactured by Sigma Aldrich) in an incubator containing 5% CO₂;detached and collected using a SERT buffer [50 mmol/L Tris-HClcomprising 120 mmol/L NaCl and 5 mmol/L KCl (pH=7.4)]; homogenized witha homogenizer manufactured by Teflon (trademark); and then centrifuged(50,000×g, 30 min, 4° C.). The precipitate was suspended again in theappropriate amount of SERT buffer (to give a membrane preparation), andstored at −80° C. until used. The amount of protein in the membranepreparation was assayed by Dye Reagent Concentrate (manufactured byBIO-RAD) using bovine serum albumin (manufactured by Sigma Aldrich) as astandard.

1-2. h-SERT Binding Assay

The [³H] citalopram binding was measured according to the methoddisclosed in Owens M. J. et al., J. Pharm. Exp. Ther., 283, 1305-1322(1997). In specific, a solution of 200 μL in total was prepared bymixing 50 μL of [³H] citalopram (manufactured by GE Healthcare) dilutedwith a SERT buffer (final concentration: about 2 nmol/L), 149 μL of theh-SERT/CHO membrane preparation (protein amount: 40 μg/well), and 1 μLof the test drug dissolved in dimethylsulfoxide. The solution wasreacted at room temperature for 60 minutes, and then quicklysuction-filtered under reduced pressure through a glass fiber filtercoated with 0.05% aq. polyethyleneimine. The glass fiber filter waswashed twice with 250 HL of the SERT buffer, placed in a plastic vialcontaining 4 mL of liquid scintillator (ACS-II, manufactured byAmersham) or Ecoscint A (manufactured by National Diagnostics), and theremaining radioactivity on the filter paper was assayed with a liquidscintillation counter. The non-specific binding of [³H] citalopram wasdefined as a binding amount in the presence of 1 μmol/L clomipramine(manufactured by Sigma Aldrich) The IC₅₀ value was calculated accordingto Hill analysis [see, Hill A. V., J. Physiol., 40, 190-200 (1910)], andthe binding inhibition constant (Ki) was calculated according to thefollowing formula:

Binding inhibition constant (Ki)=IC₅₀/(1+S/Kd)

wherein S is a concentration of the added [³H] citalopram, and Kd is abinding dissociation constant of [³H] citalopram which was calculatedfrom a saturated binding assay using the same cell membrane. A lower Kivalue (i.e. a lower h-SERT binding inhibition constant) means that thetest drug has a stronger human serotonin reuptake inhibitory action.

Test Example 2: [³H] Mesulergine Binding Assay to Evaluate Affinity forHuman 5-HT_(2C) Receptor 2-1. Preparation of the Cells and MembranePreparations

In the experiment, human serotonin 2C receptor (h-5-HT_(2C)) wasexpressed in CHO cells (h-5-HT_(2C)/CHO). The cells were incubated withUltraCHO Lipuid (trademark) (manufactured by BioWhitakker) containing 1%FBS, 400 μg/mL Geneticin, 100 U/mL penicillin—100 μg/mL streptomycin(all manufactured by Sigma Aldrich) and 250 μg/mL Zeosin (manufacturedby InvivoGen) in an incubator containing 5% CO₂; detached and collectedusing 50 mmol/L Tris-HCl (pH=7.4); homogenized with a homogenizermanufactured by Teflon (trademark); and then centrifuged (48,000×g, 25min, 4° C.). The precipitate was suspended again in the appropriateamount of 50 mmol/L Tris-HCl (to give a membrane preparation), andstored at −80° C. until used. The amount of protein in the membranepreparation was assayed by Dye Reagent Concentrate (manufactured byBIO-RAD) using bovine serum albumin (manufactured by Sigma Aldrich) as astandard.

2-2. 5-HT_(2C) Receptor Binding Assay

A solution of 200 μL in total was prepared by mixing 50 μL of [3H]mesulergine (manufactured by GE Healthcare) diluted with 50 mmol/LTris-HCl (pH=7.4) (final concentration: about 2 nmol/L), 149 μL of theh-5-HT_(2C)/CHO membrane preparation (protein amount: 20 μg/well), and 1μL of the test drug dissolved in dimethylsulfoxide. The solution wasreacted at 37° C. for 30 minutes, and then quickly suction-filteredunder reduced pressure through a glass fiber filter coated with 1% aq.bovine serum albumin. The glass fiber filter was washed twice with 250μL of 50 mmol/L Tris-HCl (pH=7.4), placed in a plastic vial containing 4mL of liquid scintillator (ACS-II, manufactured by Amersham) or EcoscintA (manufactured by National Diagnostics), and the remainingradioactivity on the filter paper was assayed with a liquidscintillation counter. The non-specific binding of [³H] mesulergine wasdefined as a binding amount in the presence of 10 μmol/L SB206553(manufactured by Sigma Aldrich). The IC₅₀ value was calculated accordingto Hill analysis, and the binding inhibition constant (Ki) wascalculated according to the following formula:

Binding inhibition constant (Ki)=IC₅₀/(1+S/Kd)

wherein S is a concentration of the added [³H] citalopram, and Kd is abinding dissociation constant of [³H] citalopram which was calculatedfrom a saturated binding assay using the same cell membrane. A lower Kivalue (i.e. a lower 5-HT_(2C) binding inhibition constant) means thatthe test drug has a higher affinity for human serotonin reuptakeinhibitory action.

Test Example 3: 5-HT_(2C) Receptor Agonistic Action Assay 3-1. The Cellsand Inoculation Thereof

In the experiment, human serotonin 2C receptor (h-5-HT_(2C)) wasexpressed in CHO cells (h-5-HT_(2C)/CHO). The cells were incubated withUltraCHO Lipuid (trademark) (manufactured by BioWhitakker) containing 1%FBS, 400 μg/mL Geneticin, 100 U/mL penicillin—100 μg/mL streptomycin(all manufactured by Sigma Aldrich) and 250 μg/mL Zeosin (manufacturedby InvivoGen) in an incubator containing 5% CO₂. On the day before usingthe cells, they were detached and collected using 250 μg/mL Trypsinsolution (manufactured by Nacalai Tesque), then inoculated in a 96 wellflat clear bottom black polystyrene TC-treated microplates (manufacturedby Corning) at 40000 cells/well/60 μL in an incubator containing 5% CO₂for 16 hours to 24 hours.

3-2. 5-HT_(2C) Receptor Agonistic Action Assay

The 5-HT_(2C) receptor agonistic action was evaluated with FLIPR Calcium4 Assay kit (manufactured by Molecular Devices). In specific, to thecells inoculated in the plate were added Component A of FLIPR Calcium 4Assay kit dissolved in 100 mL of HHBP buffer (1× Hanks buffer, 20 mmol/LHEPES, both manufactured by Gibco) at an amount of 40 μL/well, and thecells were incubated in an incubator containing 5% CO₂ for 1 hour. Then,the cells were set in FLIPR TETRA (trademark) (manufactured by MolecularDevices), to the cells was added the test material diluted with HHBPbuffer, 2.5 mmol/L Probenecid (manufactured by Sigma) (concentrationafter dilution: 10 μmol/L) at an amount of 20 μL/well, and thefluorescence was measured. Then, in order to evaluate the antagonisticaction of the test material, 20 μL/well of 5-HT solution (manufacturedby Sigma, final concentration: 0.1 nmol/L) was further added to thecells, and the fluorescence was measured.

The 5-HT_(2C) receptor agonistic action of each test material wascalculated as a rate of fluorescence enhancement wherein 100% wasdefined as a value when the cells were given 10 μmol/L 5-HT.Furthermore, the 5-HT_(2C) receptor inverse agonistic action wascalculated as a rate of fluorescence decay wherein −100% was defined asa value when the cells were given 10 μmol/L SB206553 (manufactured bySigma Aldrich). A lower value of the 5-HT_(2C) receptor agonistic actionof the test material means that the material has a higher antagonisticaction. In particular, when the value of the 5-HT_(2C) receptoragonistic action of the test material is below 0%, the material has aninverse agonistic action for 5-HT_(2C) receptor.

The present-pyrazole compounds prepared in the Examples were tested byTest Examples 1, 2 and 3, and the results thereof are disclosed in Table24. The test results clearly demonstrate that the present-pyrazolecompound and a pharmaceutically acceptable salt thereof have both humanserotonin reuptake inhibitory action and binding affinity for human5-HT_(2C) receptor, and in particular, an inverse agonistic action forhuman 5-HT_(2C) receptor.

TABLE 24 Test Ex. 2: Test Ex. 1: 5-HT_(2 c) Test h-SERT receptor Ex. 3:binding binding 5-HT_(2 c) inhibition inhibition receptor Compoundconstant constant agonistic (Ex. No.) Ki [nM] Ki [nM] action [%] 1 4.926 −86 3 12 5.4 −91 5 1.5 4.4 −91 31 0.92 5.2 −66 33 0.34 2.9 −115 424.9 31 −106 108 1.9 18 −117 115 1.5 5.4 −103 122 8.1 7.7 −117 124 0.7116 −82 131 3.7 10 −70 137 6.6 7.9 −94 144 8.3 2.2 −127 147 0.71 4.8 −105148 4.6 1.9 −102 162 7.8 14 −66 192 0.91 3.9 −90 218 9.7 10 −111 219 1.610 −127 230 2.3 4.9 −105 242 0.52 34 −95 248 4.3 9.4 −100 253 1.5 31 −86256 1.6 12 −97 258 0.66 16 −118 259 2.4 6.2 −119 266 0.69 4.5 −86 2690.59 6.7 −77 275 22 11 −88 280 1.9 9.7 −81 283 1.1 6.3 −89 284 5.7 7.9−97 286 5.5 6.6 −117 288 0.86 19 −80 315 11 3.6 −84 328 3.6 193 −116 3300.96 17 −82 331 1.3 5.9 −103 341 23 12 −71 342 8.5 14 −99 344 33 6.7 −82347 13 31 −114 349 3.0 18 −82 350 53 11 −92 351 0.98 43 −102 355 32 17−72 357 10 74 −120 381 3.4 10 −125 400 0.54 5.3 −115 405 11 23 −90 4260.99 14 −99 434 4.5 8.1 −87 435 0.60 4.4 −125 442 4.9 11 −95 446 7.4 19−89 447 0.50 13 −86 448 3.8 8.8 −94 458 5.1 21 −87 474 11 16 −111 4759.2 19 −95 476 14 2.3 −72 477 9.9 3.1 −94 481 0.85 22 −109 482 2.9 2.6−116

The present compound is a novel serotonin reuptake inhibitor which alsoexhibits 5-HT_(2C) antagonistic action, especially 5-HT_(2C) inverseagonistic action, and thus it is expected that the present compound canexhibit therapeutic effects faster than conventional compounds whichexhibit only either of the actions of the present compound.

INDUSTRIAL APPLICABILITY

The present compound is a serotonin reuptake inhibitor which alsoexhibits 5-HT_(2C) antagonistic action, especially 5-HT_(2C) inverseagonistic action, and shows potent anti-depressive and anxiolyticeffects; and thus the present compound is useful as a medicament fortreating depression or anxiety, or preventing a relapse thereof.

1. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof wherein R¹ and R² areindependently selected from the group consisting of hydrogen atom, aC₁₋₆ alkyl group and a C₃₋₈ cycloalkyl group, R³ and R⁴ areindependently selected from the group consisting of hydrogen atom and aC₁₋₆ alkyl group, R⁵ is an optionally-substituted C₄₋₇ alkyl group or—(CR⁸R⁹)_(r)-E, R⁶, R⁷, R⁸ and R⁹ are independently selected from thegroup consisting of hydrogen atom, fluorine atom and anoptionally-substituted C₁₋₆ alkyl group, A is an optionally-substitutedC₆₋₁₀ aryl group or an optionally-substituted 5- to 10-memberedheteroaryl group, r is 1, 2, 3 or 4, E is an optionally-substituted C₃₋₈cycloalkyl group, an optionally-substituted C₄₋₈ cycloalkenyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 heteroatoms independently selected from the groupconsisting of oxygen atom and sulfur atom as a constituent atom of thering, an optionally-substituted C₆₋₁₀ aryl group or anoptionally-substituted 5- to 10-membered heteroaryl group, L is oxygenatom, sulfur atom or —NR¹⁰—, n is 1, 2 or 3, R¹⁰ is hydrogen atom, aC₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group, and X is hydrogen atom, aC₁₋₆ alkyl group optionally-substituted with fluorine atom or a halogenatom.
 2. The compound of claim 1 or a pharmaceutically acceptable saltthereof wherein R¹, R² and R³ are independently selected from the groupconsisting of hydrogen atom and methyl group, and R⁴ is hydrogen atom.3. The compound of claim 1, or a pharmaceutically acceptable saltthereof wherein A is an optionally-substituted C₆₋₁₀ aryl group.
 4. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein X is hydrogen atom.
 5. The compound of claim 1 or apharmaceutically acceptable salt thereof wherein L is oxygen atom. 6.The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein n is
 1. 7. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R¹, R³ and R⁴ are hydrogen atom, and R²is methyl group.
 8. The compound of claim 1 or a pharmaceuticallyacceptable salt thereof wherein R⁶, R⁷, R⁸ and R⁹ are hydrogen atom. 9.The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein E is an optionally-substituted C₃₋₈ cycloalkyl group, anoptionally-substituted 5- to 10-membered saturated heterocyclic groupwhich comprises 1 to 3 oxygen atoms as a constituent atom of the ring,or an optionally-substituted phenyl group.
 10. The compound of claim 1or a pharmaceutically acceptable salt thereof wherein E is anoptionally-substituted C₃₋₈ cycloalkyl group.
 11. The compound of claim1 or a pharmaceutically acceptable salt thereof wherein r is 1 or
 2. 12.The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁵ is an optionally-substituted C₄₋₇ alkyl group.
 13. Thecompound of claim 1 wherein the compound of Formula (1) is any one ofthe following compounds, or a pharmaceutically acceptable salt thereof:1-[5-(benzyloxy)-1-(cyclohexylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(3-chlorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclohexylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-[5-(benzyloxy)-1-(cyclopentylmethyl)-1H-pyrazol-3-yl]-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(3-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(3-chlorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(3-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2,4-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-4-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(4-fluoro-2-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2-fluoro-5-methylbenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-5-fluorobenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2,5-dichlorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-chloro-5-methylbenzyl)oxy]-1-(cyclopentylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-[5-(benzyloxy)-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;1-{5-[(3-chlorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3,3-dimethylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-[5-(benzyloxy)-1-(3-methylbutyl)-1H-pyrazol-3-yl]-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-methoxy-3-methylbutyl)-1H-pyrazol-3-yl)}-N-methylmethanamine;1-{1-(cyclopentylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(cyclohexylmethyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;N-methyl-1-{1-(3-methylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;1-{1-(3,3-dimethylbutyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(4-fluorobenzyl)-5-[(2-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-fluorobenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(4-fluorobenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-fluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methylbenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;N-methyl-1-{1-(4-methylbenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}methanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(4-methoxybenzyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(4-methoxybenzyl)-5-[(2,4,5-trifluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(cyclopropylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(4-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2-methylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{1-(2,2-dimethylpropyl)-5-[(4-fluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(2,2-dimethylpropyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(2-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-{5-[(4-fluorobenzyl)oxy]-1-(3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;1-(5-[(4-fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanamine;1-(5-[(2,5-difluorobenzyl)oxy]-1-{[1-(trifluoromethyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanamine;1-(5-[(5-chloro-2-fluorobenzyl)oxy]-1-{[1-(trifluoromethyl)cyclopentyl]methyl}-1H-pyrazol-3-yl)-N-methylmethanamine;(−)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;(+)-1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-3-yl}-N-methylmethanamine;(−)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;(+)-1-{1-(2-cyclopentylethyl)-5-[(2,5-difluorobenzyl)oxy]-1H-pyrazol-3-yl}-N-methylethanamine;1-{5-[(2,5-difluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine;or1-{5-[(5-chloro-2-fluorobenzyl)oxy]-1-(3-fluoro-3-methylbutyl)-1H-pyrazol-3-yl}-N-methylmethanamine.14. A medicament comprising the compound of claim 1 or apharmaceutically acceptable salt thereof as an active ingredient. 15.The medicament of claim 14 which is used for treating depression oranxiety, or preventing a relapse thereof.
 16. A serotonin reuptakeinhibitor comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof as an active ingredient.
 17. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.